(S1P1) Agonists and - ACS Publications - American Chemical Society

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Modulators of Sphingosine-1-phosphate Pathway Biology: Recent Advances of Sphingosine-1-phosphate Receptor 1 (S1P1) Agonists and Future Perspectives Alaric J. Dyckman* Research and Development, Bristol-Myers Squibb Company, P.O. Box 4000, Princeton, New Jersey 08543-4000, United States ABSTRACT: The sphingoid base derived class of lipids (sphingolipids) is a family of interconverting molecules that play key roles in numerous structural and signaling processes. The biosynthetic pathway of the sphingolipids affords many opportunities for therapeutic intervention: targeting the ligands directly, targeting the various proteins involved in the interconversion of the ligands, or targeting the receptors that respond to the ligands. The focus of this article is on the most advanced of the sphingosine-related therapeutics, agonists of sphingosine-1-phosphate receptor 1 (S1P1). The diverse structural classes of S1P1 agonists will be discussed and the status of compounds of clinical relevance will be detailed. An examination of how potential safety concerns are being navigated with compounds currently under clinical evaluation is followed by a discussion of the novel methods being explored to identify nextgeneration S1P1 agonists with improved safety profiles. Finally, therapeutic opportunities for sphingosine-related targets outside of S1P1 are touched upon.

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INTRODUCTION Lipid signaling has long been recognized as an important contributor to human health, with its proper function critical to maintaining homeostasis and dysregulation contributing to the pathogenesis of varied diseases and disorders.1 In recent years, the complexity of this signaling has continued to be appreciated, with an expanded understanding of the types of ligands, the pathways involved in their biosynthesis, distribution and degradation, and the exquisite temporal and spatial control of the production of both the ligands and their protein targets. The sphingolipids, named in reference to the mythological sphinx, are one group of signaling lipids for which the last two decades has seen exceptional scientific breakthroughs delineating their key roles in processes such as apoptosis, cell-cycle arrest, cell proliferation, and cell migration.2 For many aspects under the control of sphingolipid signaling, a balance is struck in response to various members of the family in what was termed the “sphingolipid rheostat”, with the actions of one family member being counteracted by another.3 For example, while ceramides and sphingosine are pro-apoptotic and involved in growth arrest, another key messenger from this family, sphingosine-1-phosphate (S1P), promotes growth and survival.4 The generation and interconversion of these and other sphingolipids is outlined in Figure 1. The de novo synthesis of the sphingolipids starts with the condensation of serine and palmitoyl CoA to form 3-ketosphinganine, which is further transformed in a multistep process to ceramides.5 Ceramides reversibly interconvert to sphingosine via ceramidase and ceramide synthase, with sphingosine being reversibly transformed to S1P via the action of sphingosine kinases and S1P phosphatases. The interconversion of ceramides, sphingo© 2017 American Chemical Society

sine, and S1P requires careful control of the equilibrium of this lipid pool to maintain homeostasis in living organisms. Within the sphingolipid family, S1P has garnered notable attention in recent years for drug discovery efforts as the targets of its signaling have been further characterized. Originally thought to be important solely for intracellular signaling, an extracellular role for S1P was first defined in 1998 with the deorphanization of the endothelial differentiation gene 1 (Edg1) G protein-coupled receptor (GPCR), noting S1P as a high affinity ligand.6 Four additional Edg GPCRs were found to be activated by S1P, with the family being renamed as the receptor subtypes S1P1−5.7 Acting on this set of receptors, S1P has been shown to regulate the cardiovascular, immune, and nervous systems, through impacting a diverse array of physiological processes such as modulation of cellular barrier integrity, maintenance of vascular tone, and directing cellular trafficking.8 Intracellular targets for this lipid include those with cytosolic (TRAF1, cIAP2) and nuclear (HDAC1, HDAC2) localizations.9 S1P can be produced intracellularly in all cell types, with erythrocytes and vascular endothelial cells serving as major sources for the plasma.10 Platelets have also been identified as sources for plasma S1P but only when activated or under inflamed conditions.11 Plasma concentrations of S1P range from approximately 200−900 nM; however, it is highly protein bound, with free circulating S1P in the very low nanomolar concentrations.12 While albumin is responsible for binding of a portion of plasma S1P (∼30%), binding to lipoproteins is noted Received: October 24, 2016 Published: March 14, 2017 5267

DOI: 10.1021/acs.jmedchem.6b01575 J. Med. Chem. 2017, 60, 5267−5289

Journal of Medicinal Chemistry

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Figure 1. Biosynthetic and degradative pathways of sphingosine-1-phosphate.

Figure 2. From myriocin to fingolimod.

as the major repository.11 Of the lipoproteins (HDL, LDL, VLDL), the majority of S1P is found associated with HDL particles bearing apolipoprotein M (Apo-M), with Apo-M being responsible for the direct binding of S1P, as HDL particles lacking Apo-M do not associate with S1P.13 Quite interestingly, a recent report indicates that the nature of the chaperone is far from innocuous, appearing to significantly direct the signaling, and therefore the biological effects, of S1P.14 In that report, albumin-S1P and HDL-S1P both induced phosphorylation of ERK; however, cAMP elevations were inhibited by albumin-S1P but not by HDL-S1P, whereas βarrestin 2 association was driven by HDL-S1P but not by albumin-S1P. This ligand-biased signaling directed by the protein chaperones introduces yet another level of complexity to the way in which sphingolipids are utilized to modulate biological processes. The high plasma concentration of S1P stands in contrast to its very low tissue concentrations (∼10 nM) and moderate lymph concentrations (∼1/4 the plasma concentration).15 This concentration gradient, made possible in part by careful regulation of degrading enzymes (S1P lyase, S1P phospha-

tases), is a critical component of some of the biological functions of S1P (see below for discussion of S1P/S1P1 interactions). As discussed above, S1P’s biological actions are a direct outcome, in large part, to the activation of S1P1−5. As such, the bulk of drug discovery efforts have been aimed at controlling that interaction through the identification of modulators (agonists or antagonists) of each of the GPCRs, with varying levels of specificity and cross-reactivity. In the sections below, medicinal chemistry efforts and, where applicable, clinical activities are reviewed, with a primary focus on the most heavily investigated area of S1P1 agonists.

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S1P1 AGONISTS: METABOLICALLY ACTIVATED (“PRO-DRUG”) LIGANDS Having been first described in 1990 as the endothelial gene related protein Edg-1, the recognition that S1P1 was the molecular target responsible for the compelling in vivo efficacy of the clinical drug candidate fingolimod (Figure 2; 2, FTY720) marked the beginning of an explosion of interest in this 5268



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receptor as a drug target.16 The discovery of fingolimod, with an initially unknown mechanism of action, is a remarkable story of serendipity combined with the tremendous effort involved in an in vivo based screening paradigm. Myriocin (Figure 2; ISP1) is a natural product that was isolated from a parasitic fungus that attacks insects, with the fungus noted for its use in traditional Chinese herbal medicines.17 Myriocin was observed to have immunosuppressant activity that was 10−100-fold more potent than cyclosporine and showed efficacy in a rat skin allograft model.18 Because of the narrow therapeutic window between efficacy and overt toxicity, along with the poor aqueous solubility of myriocin, a medicinal chemistry effort was initiated to optimize this structure.19 Critically, the optimization effort relied heavily on an in vivo driven approach, including the use of a rat skin allograft model, as the discrete molecular target of myriocin was not known at the time. Through an iterative simplification process outlined in Figure 2, the highly polar amino-acid/triol motif of myriocin was reduced to an aminodiol group, then combined with a fully saturated alkyl tail to afford 1, which was found to be both more efficacious in vivo than myriocin and also less toxic.20 Introduction of an aryl group, to provide conformational restriction and also a convenient chromophore for analytical detection, followed by optimization of the chain lengths and aryl placement, led to fingolimod, a compound with good solubility, a favorable toxicity profile, and superior in vivo activity as compared to either 1 or myriocin. Subsequent to these efforts, a key molecular target of myriocin was deduced as serine palmitoyltransferase (SPT), the enzyme involved in the initial step of the biosynthesis of sphingolipids (see Figure 1).18,21 Ironically, the medicinal chemistry optimization of myriocin led to analogues (e.g., 1 and fingolimod) that were essentially devoid of activity against SPT20 despite maintaining the desired in vivo readout. Had a traditional target-based optimization effort been utilized, the structure−activity path from myriocin to fingolimod would not have been followed. The observed in vivo efficacy of fingolimod was later determined to depend upon its bioconversion to an active metabolite (Figure 3). In vivo, fingolimod undergoes stereo-

phosphorylation rate is just one of the challenges associated with progressing agonists of the pro-drug class into clinical development. The immunosuppressive effects of fingolimod were attributed to the compound-induced reduction of circulating blood lymphocytes (lymphopenia), an effect that was ultimately found to be a result of its action on S1P receptor subtype 1.24 Although acting as an agonist at the S1P receptors, activation of S1P1 by fingolimod-P results in prolonged receptor internalization and degradation rather than recycling back to the surface as happens after activation with the endogenous ligand.25 The result is a pharmacologic “null-state” wherein S1P1 has been deleted from the cell surface. The interaction of S1P with S1P1 is a key determinant of migration out of specific compartments for a number of cell types. Notably, many lymphocyte subsets rely on cell surface S1P1 to detect the gradient of S1P that is maintained from the lymphatic system to the blood in order to migrate into circulation.26 In response to the functional antagonism of fingolimod-P, these cells lose the ability to migrate and are entrapped in the thymus and secondary lymphoid organs. In diseases marked by an aberrant immune response, this sequestration of lymphocytes has been shown to provide significant benefit based on responses in animal models and emerging clinical data with S1P1 agonists.27 In addition to the lymphopenia that is mediated through functional antagonism of S1P1, the effects of directly agonizing the S1P receptors within the CNS have also been evaluated, particularly for S1P1 and S1P5. For CNS disorders, such as multiple sclerosis, those effects could be significantly beneficial and therefore the ability of the agonist to cross the blood−brain barrier (BBB) would be important. For application to non-CNS disorders, compounds with peripherally restricted distribution might be preferred so as to avoid off-target concerns of unnecessary CNS exposure. Fingolimod and similar analogues have been shown to be highly distributed, including into the CNS compartment. With other classes of agonists, BBB penetration is a property that is commonly, but not always, reported on. As discussed below (see S1P1 Agonists: Clinical Development), the clinical utility of fingolimod treatment has been demonstrated in multiple sclerosis and organ transplantation and is being pursued for a variety of additional indications (see Table 1). Clinically relevant safety concerns that have been noted with fingolimod include cardiovascular effects (transient reduction in heart rate, some incidence of atrioventricular (AV) conduction issues, and mild but sustained elevation of blood pressure), asymptomatic alanine transaminase (ALT) and bilirubin increases, a low incidence of macular edema, decreased performance in pulmonary function tests, and a long half-life (∼7 days) which results in an extended wash out period upon drug discontinuation (approximately 3 months was needed for most patients to recover to 80% of baseline lymphocyte levels).28 The continued preclinical and clinical success of fingolimod spurred on an extraordinary effort by many research teams over the past decade and a half to identify agonists of S1P1 with improved properties, such as increased receptor selectivity, reduced pharmacokinetic half-life, and an enhanced safety profile. As discussed below (see Next Generation of Safety), early data suggested that deletion of agonist activity on S1P3 would improve cardiovascular safety. While this was not borne out in the clinic, likely due to species differences between rodent and human in S1P signaling,29 the goal of identifying S1P3-sparing agonists remains a theme throughout most

Figure 3. Stereospecific bioconversion of fingolimod to fingolimod-P.

selective phosphorylation to form (S)-fingolimod-P (3), utilizing one of the enzymes (sphingosine kinase 2, SK2) that converts sphingosine to S1P as the primary means for this transformation.22 The resulting phosphate binds with high affinity to and activates four of the five S1P receptors (S1P1,3,4,5).23 The efficiency of the conversion was found to vary among species, with the phosphorylation rate of fingolimod in human blood being notably lower than in either rat blood or mouse blood. 22b This species-dependent 5269



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Figure 4. Pro-drug agonists of S1P1 inspired by fingolimod.

A series of disclosures originating at the University of Virginia highlights a different constraint of the polar headgroup, this time through the incorporation of a cyclopentyl system containing the requisite amino-alcohol in VPC01091 (9).34 Quite interestingly, when the four diastereomers of 9 were separated, the in vivo and in vitro biology were noted to be quite variable. The isomers bearing an (S) configuration at the amino center (10, 11) were unable to be phosphorylated by sphingosine kinase 2 and as such were not able to induce lymphopenia in rodents. However, the isomers of the (R) configuration (12, 14) were phosphorylated in vivo and produced robust and long lasting lymphopenia. The phosphates of both 12 and 14 were characterized as potent but partial agonists of S1P1 in a GTPγS assay, and the phosphate of 14 (bearing the (S) configuration at the benzylic center) introduced antagonism against S1P3. This same cyclopentyl constraint later appeared in a disclosure from Abbott which highlighted an aryl ketone compound (16).34c The constraint was also incorporated in tricyclic compounds 17 and 1835 and can be found in a clinical development compound (see 60 in Figure 8). Additional permutations of the fingolimod pro-drug scaffold can be seen in other clinical or late-stage preclinical development compounds shown in Figures 8 and 9 (see 49, 56, 62, 75, and 79).

discovery efforts. An early and logical route to analogue design was to mimic the key structural elements of fingolimod, retaining the amino-alcohol group and the metabolically activated (“pro-drug”) nature of the compounds while manipulating virtually every other region of the molecule (Figure 4). It was found that one of the hydroxyls in fingolimod could be deleted, with the chirality of the resulting quaternary center influencing the ability of the remaining alcohol to be phosphorylated.23b,30 Furthermore, the phenyl core was able to be replaced with other aryl or heteroaryl mono- or polycyclic systems, and constraints could be imposed upon both the lipophilic and polar regions. Several such changes are illustrated in the imidazole analogue 4, which is a potent and selective agonist of S1P1/5 with selectivity over S1P2,3,4.31 Data on the in vivo bioconversion to 4 from the amino-alcohol precursor has not been disclosed. A tetralin constraint could be introduced either through conceptual cyclization onto the terminal methyl group of the aminoethanol alkyl chain (path a in 6 to give 5) or through cyclization onto a methylene carbon of the chain (path b in 6 to give 7/8). Tetralin 532 provided an apparent submaximal level of lymphopenia in mice even at a high dose (64% reduction after four daily intraperitoneal injections of 30 mg/kg), which is well below the in vivo potency of tetralin 733 (mouse lymphopenia ED50 = 0.1 mg/kg), indicating that the direct attachment of the aminoethanol fragment to the tetralin is not as favorable. While 7 did afford some receptor selectivity (phosphate S1P1 EC50 1.79 nM; S1P3/S1P1 = 54), incorporation of an ortho-CF3 and elaboration of the lipophilic tail of this template led to 8, which retained much of the on-target activity (S1P1 EC50 5 nM) while eliminating agonist activity against S1P3 up to a top-tested concentration of 1 μM.

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DIRECT-ACTING AGONISTS OF S1P1 A second major class of compounds emerged through the rationally designed replacement of the zwitterionic aminophosphate of the active metabolite fingolimod-P with stabilized polar functionality that lacked the requirement for bioactivation. These direct-acting agonists avoid the complications 5270



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Figure 5. Evolution of amino-phosphate mimics as S1P1 agonists.

azetidine carboxylate fragment was subsequently combined with a lipophilic aryl framework such as found in SEW2871 (27), a series that had been identified through high throughput screening efforts, to afford highly potent and selective S1P1 agonists with significant oral activity (murine PLL 3 h ED50 0.44 mg/kg for 28 and 0.03 mg/kg for 29).38,39 The azetidine carboxylate has since become one of the most successful and replicated polar headgroups utilized for S1P1 direct-acting agonist design. As can be seen in the structures of clinical or late-stage preclinical compounds (Figures 8 and 9), this motif appears directly in seven of these important molecules and its influence is evident in the design of the polar headgroup utilized by several other compounds. Similarly, it is easy to notice the legacy of compounds such as 27, 28, and 29 in the aryl/lipophilic frameworks of the majority of the compounds presented in Figures 8 and 9. The S1P1 receptor has been found to be exceptionally accommodating to synthetic agonists of diverse structure, and direct-acting agonists of S1P1 have been widely explored to identify the minimum required elements for robust activity. The polar headgroup, initially zwitterionic in nature, was found to be replaceable with singly charged headgroups, with either acidic or basic groups finding success. Furthermore, polarneutral headgroups have been successfully advanced. Even neutral, nonpolar headgroups could be utilized to bring in reasonable, if not optimal, activity against S1P1 as highlighted above with 27. The accommodating nature of S1P1 left the boundaries of analogue design limited predominantly by the creativity of the numerous research teams that have been active in this area. Shown below (Figures 6 and 7) are representative examples of these classes of direct-acting S1P1 agonists that serve to highlight the creativity that has come into play. Polar-Zwitterionic. The majority of the near-clinical and clinical-stage direct-acting S1P1 agonists (Tables 1, 2) utilize zwitterionic headgroups, and it has been highly represented in

associated with species-dependent phosphorylation and reduce the complexity of clinical development in comparison to prodrugs, where both the parent and metabolite must be monitored for PK and safety. Pioneering efforts on the identification of direct-acting agonists of S1P1 were conducted in the Merck laboratories (see Figure 5). Replacement of the metabolically labile phosphate of fingolimod-P with a stabilized phosphonate (19) resulted in a 30−40-fold reduction in binding affinity for S1P1 and S1P3; however, compound 19 was still able to replicate the in vivo pharmacodynamic (PD) effects of fingolimod/fingolimod-P.23a Intravenous (IV) administration of 19 to mice induced significant peripheral lymphocyte lowering (PLL; “lymphopenia”) at 3 h postdose. A similar phosphate to phosphonate switch was used on simplified analogue 20 to give 21. A 10-fold reduction in S1P1 binding was noted, but there was a more pronounced loss in activity on S1P3, leading to improved receptor selectivity for phosphonate 21.36 Addition of a hydroxyl group α to the phosphonate, as in 22, significantly improved activity against S1P1 and provided a similar level of PD activity as compared to phosphate 20 after IV dosing. In a closely related series (23−26), attempts were made to replace the phosphate with other stabilized, acidic functionality including phosphinic acid 24 and carboxylic acid 25.37 The binding affinity for S1P1 was reduced by about 40fold for carboxylate 25 relative to phosphonate 23, but 25 showed excellent selectivity against S1P3. Carboxylate 25 also provided hope that oral bioavailability could be achieved in a phosphate mimic, as prior in vivo work was limited to intravenous (IV) or intraperitoneal (IP) routes of administration. The design of constrained analogues then led to the discovery of azetidine carboxylate 26.38 While the binding affinity of 26 for S1P1 was modest in comparison to the earlier zwitterionic compounds, oral bioavailability in mice was very good (>70%) and 26 was able to induce lymphopenia after oral dosing, with an ED50 of 5.2 mg/kg at the 3 h time point. This 5271



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Figure 6. Additional polar-zwitterionic direct-acting agonists of S1P1.

Figure 7. S1P1 agonists from the acidic, basic, neutral, and nonpolar classes.

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Figure 8. S1P1 agonists with reported clinical entry and disclosed structure.

nonoral delivery such as topical or ocular routes of administration. For compounds 34 and 35, the orientation of the polar and lipophilic groups across the phenyl group is changed from the more typical para- relationship to a metaorientation.44 Although only rough potency ranges from a calcium mobilization assay were provided, it is intriguing that while both compounds were described as S1P1 agonists and S1P4 antagonists, the relatively subtle modifications from 34 to 35 (including a constraint added to the polar headgroup and a change in the projection of the lipophilic cyclohexyl tail) led to a switch in S1P5 activity from an agonist (34) to an antagonist (35). Furthermore, while 34 was claimed as an inhibitor of autotaxin (ATX), no such claim was made for 35. It will be exciting to see further disclosures highlighting the SAR of this series with regard to S1P receptor family and ATX activity. While the polar-zwitterionic class has dominated the reports of direct-acting S1P1 agonists over the past decade, notable examples (including clinical compounds) have emerged from the other categories. Highlighted below and shown in Figure 7 are representative compounds from these classes. Polar-Acidic. With an optimally substituted biphenyl lipophilic group, the truncation of the polar headgroup to a benzoic acid (36) provided a compound with potent binding to

continuing disclosures. A pair of unrelated amino-thiadiazoles (Figure 6; 30 and 31) highlights the diversity that has been successfully explored in the aryl linker region of the polarzwitterionic class. While utilization of a variety of fivemembered heteroaryl systems as central linkers has found widespread acceptance in S1P1 agonist design, the vast majority of examples incorporate carbon−carbon bond attachments to the polar and lipophilic sides of the heteroaryl core. In contrast, the lipophilic tail of 30 was appended to the thiadiazole via amino substitution, with the exocyclic amine incorporated as a benzamide.40 Similarly, in 31, the thiadiazole central ring connects to the amino acid headgroup via an N-linked pyrazolebased bicycle.41 In each case, excellent potency on S1P1 and selectivity against S1P3 were maintained. In example 32, the polarity of the zwitterionic group was taken even a step further with the addition of a second carboxylate, which surprisingly retained oral activity in a mouse model of lymphopenia.42 Example 33 demonstrates that the original stabilized phosphate mimetics, the amino-phosphonates, continue to make appearances in disclosures.43 While mouse lymphopenia of 33 was only demonstrated through subcutaneous (sc) injection, indicating that oral bioavailability may remain poor for this series, it is possible that the interest in these compounds lies in 5273



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Figure 9. S1P1 agonists of advanced preclinical development.

S1P1 (Ki 2.9 nM) and only weak affinity for S1P3.45 On the same template, extension of the acidic group further from the phenyl ring led to a 3-fold increase in S1P1 binding activity while maintaining selectivity against S1P3 in 37. In 38, an early member of the series that ultimately led to the polar-acidic clinical compound etrasimod (Figure 8; 58), the pendant carboxylic acid is attached to an indoline that serves as the central aromatic system.46 Additional clinical or near-clinical compounds of this category are 64, 67, and 68 (Figures 8 and 9). Polar-Basic. The molecules of advanced status within this category are benzimidazole 59 (Figure 8), a phase I clinical compound, and ozanimod (Figure 8; 54), which has reached phase III. Additionally, a large number of S1P1 agonists have been described in which the polar headgroup relies on either highly basic amines or weakly basic heteroaromatic systems. For example, replacement of the central phenyl ring with a substituted pyridine (39) provided a compound capable of inducing lymphopenia in rats after oral dosing.47 In the structurally unique diphenylethyne compound 40, a pendant imidazole serves as the headgroup to provide a potent S1P1 agonist.48 With a basic amino-alcohol polar group, phenyl ether 41 was designed to be a potent direct-acting S1P1 agonist and it was shown to elicit lymphopenia in rats after oral dosing.49 When explored in more detail, 41 was also found to be a competent substrate for phosphorylation, with circulating levels

of the active metabolite 42 actually predominating over the levels of the parent and likely being more responsible for the observed PD effect. Given the above discussion of aminothiadiazoles 30 and 31 (Figure 6), it is worth drawing attention to the lipophilic portion of 41 in which the seldom utilized amino-heteroaryl system was also incorporated. Polar-Neutral. Research at Actelion Pharma, concurrent with the early Merck efforts, identified a diol headgroup that contrasts with the diol of fingolimod in that it does not require bioactivation for engagement of S1P 1. This moiety was successfully employed in the clinical compounds ponesimod and cenerimod (Figure 8; 52 and 53) as well as in a related manner with ACT-209905 (Figure 9; 69).50 The Actelion diol motif has been exploited in the design of numerous other S1P1 agonists in the field. Additional representative polar-neutral agonists include those in which the central phenyl ring was replaced with a pyridone such as 43 and 44, developed by unrelated research efforts.51,52 Although the orientation of the pyridone differs between the two compounds, each is able to make efficient interaction with S1P1 based upon the reported binding or agonist functional assay data. Amides of a mandelic acid fragment formed the neutral headgroup of a series that included compound 45.53 The (S)-hydroxyl moiety of this series was found to be important for optimal S1P1 potency, with either deletion or inversion found to be detrimental to S1P1 activity.54 5274



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Table 1. S1P1 Agonists with Reported Clinical Development company Novartis/ Mitsubishi

compd code FTY720

Novartis/Kyorin

KRP203

Novartis

BAF312

Actelion

ACT-128800

name: nonproprietary (marketed) fingolimod (Gilenya)

siponimod

ponesimod

S1PR selectivitya 1,3,4,5

highest phase reached

indication(s)

b

pro-drug or direct acting

structurec

pro-drug

2

key refs and clinical trial infod

marketed

RRMS

III III

CIDP PPMS

III

transplant

II

ALS

1,5

II II II

Crohn’s UC SCLE

pro-drug

49

ref 62d JapicCTI-132108 NCT01375179 NCT01294774

1,5

III II

SPMS RRMS

direct

51

II II

polymyositis dermatomyositis

ref 29 NCT01665144 (EXPAND) NCT00879658 (BOLD) NCT01801917 NCT02029274

III II

RRMS GvHD

direct

52

II

psoriasis

ref 50a NCT02425644 (OPTIMUM) NCT02461134 NCT00852670; NCT01208090

1,(3,5)

ref18−20 NCT00289978 NCT01625182 (FORCIDP) NCT00731692 (INFORMS) NCT00239876 NCT01786174

Actelion

ACT-334441

cenerimod

NDe

II

SLE

direct

53

ref68b, 90 NCT02472795; AC-064A201

Receptos/Celgene

RPC1063

ozanimod

1,5

III III

RRMS UC

direct

54

II

Crohn’s

ref 69d NCT02294058 (SUNBEAM) NCT02435992 (TRUE NORTH) NCT02531113 (STEPSTONE)

Ono

ONO-4641

ceralifimod

1,5

II

RRMS

direct

55

ref 72b. NCT01081782 (DreaMS)

Mitsubishi Tanabe

MT-1303

amiselimod

1

II II

RRMS SLE

pro-drug

56

II II

Crohn’s psoriasis

ref 74 NCT01742052 (MOMENTUM) NCT02307643 NCT02378688 NCT01987843

1,(5)

II

UC

direct

58

ref 75a NCT02447302

I I/II

ND direct

ND ND

direct

59

Arena

APD334

etrasimod

AbbVie Akaal Pharma

ABT-413 AKP-11

1,5

Astellas

ASP4058

1,5

I

5275

psoriasis, atopic dermatitis (topical)

ref 78 ACTRN12616000293460 ACTRN12616000922471 ref 79 NCT01998646



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Table 1. continued company

compd code

Bristol-Myers Squibb

BMS-986104

name: nonproprietary (marketed)

S1PR selectivitya 1,4,5

highest phase reached

indication(s)

I

b

pro-drug or direct acting

structurec

pro-drug

60

key refs and clinical trial infod ref 81 NCT02211469

Daiichi-Sankyo

CS-0777

1 [ND:2,4,5]

I

MS

pro-drug

62

ref 82a NCT00616733

GlaxoSmithKline

GSK2018682

1,5

I

MS

direct

64

ref 83 NCT01431937

Pfizer

PF-462991

1 [ND:2,4,5]

I

RA

direct

65

ref 84 NCT00797342

Suzhou Connect

CBP-307

ND

I

direct

66

ref 87 NCT02280434

a

Activity on the S1P1−5 receptors is noted with those in parentheses indicating reduced relative activity. bRRMS, relapsing remitting multiple sclerosis; CIDP, chronic inflammatory demyelinating polyradiculoneuropathy; PPMS, primary progressive multiple sclerosis, ALS, amyotrophic lateral sclerosis; UC, ulcerative colitis; SCLE, subacute cutaneous lupus erythematosus; SPMS, secondary progressive multiple sclerosis; GvHD, graft versus host disease; SLE, systemic lupus erythematosus; MS, multiple sclerosis; RA, rheumatoid arthritis. cSee Figure 8 for corresponding structure. d Clinical trial identifier and associated trial name. eND, not disclosed.

Nonpolar. This is perhaps an overly simplified name for this category, as compounds of a purely lipophilic nature bring rather modest activity against S1P1 and poor selectivity against S1P3. This is evidenced by the functional activity of unsubstituted phenyl analogue 46 in S1P1 and S1P3 GTPγS assays.55 Incorporation of substituents with some polarizability is required to gain notable potency/selectivity. Even for the prototypical compound of the class, 27, the polarizability of the trifluoromethyl group has been invoked as adding to its ability to replace the salt-bridge polar interactions of classical headgroups in the binding pocket of S1P1 with ion−dipole interactions.56 Adding methoxy and halogen substitution to the phenyl group was sufficient to improve activity against S1P1, as in 48,49 and more notably in compound 47 (S1P1 EC50 6 nM in a GTPγS assay).57 While decent activity can be achieved in this class, the addition of a polar headgroup of any type invariably leads to improved potency and selectivity as can be seen by comparing 48 to the more advanced member of this series, 41. Consistent with this, all clinical or near-clinical compounds disclosed thus far utilize some polar headgroup, with no reports of nonpolar agonists of advanced status.

1. The corresponding structures, where reported, of clinical stage S1P1 agonists are shown in Figure 8. The entry of generic versions of fingolimod to the market is likely to occur in 2019, which could have an impact on the development plans of other S1P1 agonists. Fingolimod was previously advanced to phase III evaluation for the prevention of renal transplant rejection but was not superior to the standard of care.58 More recently, a phase III study in patients with primary progressive multiple sclerosis (PPMS) was completed. In the largest trial ever conducted in this population, the INFORMS trial did not meet the primary end point of reducing disability progression in PPMS patients.59 Fingolimod was also separately advanced to a phase III trial for chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) and a phase IIa trial for amyotrophic lateral sclerosis (ALS).60,61 Novartis has progressed two follow-up S1P1 agonists into clinical development in both the pro-drug class (49, KRP203) and direct-acting agonist class (51, BAF312, siponimod).62−65 In partnership with Kyorin, 49 has been evaluated in phase II trials for subacute cutaneous lupus erythematosus (SCLE), ulcerative colitis (UC), and Crohn’s disease.62 With siponimod, the safety and MRI-based efficacy of a phase II trial for RRMS were found to warrant progression of the compound to phase III for that indication.63 In the phase III EXPAND study in patients with secondary progressive multiple sclerosis (SPMS), siponimod met the primary end point of reducing disability progression versus placebo.64 Two additional indications, polymyositis and dermatomyositis, are being evaluated with siponimod in separate phase II trials after a phase IIa proof of concept trial in combined myositis patients suggested beneficial effects of drug treatment in those populations.65 Actelion has reported on the progression of two S1P1 modulators, both direct-acting agonists, into clinical trials. Ponesimod (52, ACT-128800) was evaluated in phase II studies for patients with psoriasis and is currently being evaluated in a phase II trial for chronic graft versus host disease (GvHD).66 The most advanced clinical trial with ponesimod is

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S1P1 AGONISTS: CLINICAL DEVELOPMENT Although fingolimod (2) remains as the sole marketed S1P1 agonist (approved in 2010 by the FDA for the treatment of relapsing remitting multiple sclerosis (RRMS)), the past decade has seen a growing list of members of this class enter and progress through human clinical trials. In Table 1 are listed the compounds for which clinical trial entry has been disclosed. Some of these compounds have subsequently been dropped from development and others may be presumed to have been dropped based on lack of recent reporting. Nevertheless, the highest phase that was reported to have been reached for the indications disclosed is captured in the table as well. Where available, the selectivity within the S1P receptor family is noted. A hallmark of second-generation S1P1 agonists is maintaining at least some selectivity against S1P3, although a full selectivity profile has not been provided for all of the compounds in Table 5276



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Table 2. S1P1 Agonists with Reported Advanced Preclinical Development Activity company AbbVie Actelion Amgen/Predix Bristol-Myers Squibb Bristol-Myers Squibb Bristol-Myers Squibb Daiichi-Sankyo GlaxoSmithKline/Praecis GlaxoSmithKline Meiji Seika/Curadim Merck Serono Novartis

compd code compd 1/2 ACT-209905 AMG-369 BMS-520 compd 19b compd 10 CS2100 GSK1842799 GSK2263167 CP-9531 compd 49 compd 1

S1PR selectivitya d

ND ND 1,5 1,4,5 1,4,5 [2 ND] 1,4,5 [2 ND] 1,4,5 1,4,5 [2 ND] 1 [ND:2,4,5] ND 1,5 ND

pro-drug or direct-acting

structureb

refc

direct direct direct direct direct direct direct pro-drug direct direct direct pro-drug

67, 68 69 70 71 72 73 74 75 77 ND 78 79

88 89, 90 91, 92 93 94 95 96, 97 98, 99 100 123, 125 45 101

a

Activity on the S1P1−5 receptors is noted. bSee Figure 9 for corresponding structure. cCorresponding reference for further information. dND, not disclosed.

dermatitis.77 The choice of topical administration is not due to oral bioavailability limitations of 84, as it was separately reported to be orally active in a mouse model of multiple sclerosis.78 Progression with topical application could help navigate common side effects of S1P1 agonists, as systemic circulation of 84 would be largely avoided. ASP4058 (59), a direct-acting agonist in which a benzimidazole serves as the polar-basic headgroup, was progressed by Astellas into phase I evaluation.79 Astellas subsequently reported that 59 had been dropped from further development.80 Bristol-Myers Squibb has disclosed the phase I evaluation of BMS-986104 (60), a pro-drug modulator of S1P1,4,5 whose phosphate displayed partial agonist activity against S1P1 and was described as having predicted improvements to pulmonary safety based on rodent in vivo data and cardiovascular safety based on a human-relevant in vitro cardiomyocyte assay.81 CS-0777 (62), a pro-drug agonist that shows selectivity against S1P3, was progressed by DaiichiSankyo through a 12-week phase I evaluation in multiple sclerosis patients.82 In addition to the desired pharmacology (lymphocyte reduction), treatment with 62 was associated with mild bradycardia and transaminase elevations, findings reminiscent of those observed with the nonselective S1P agonist fingolimod. Further development of 62 has not been reported. The results of three phase I studies with GSK2018682 (64), a direct-acting S1P1,5 agonist from GlaxoSmithKline, have been reported.83 Along with single-dose and repeat-dose evaluations of the PK, PD, and tolerability of 64, an additional study focused on bioavailability of various formulations of a 2 mg dose under fed and fasted conditions. Cardiovascular effects (bradycardia, AV block) and transient elevation of liver enzymes were among the undesired effects noted with 64. Pfizer’s direct-acting agonist PF-462991 (65) entered phase I evaluation, and while RA was stated as the ultimately desired indication, progression to further clinical study was not revealed.84 Finally, Suzhou Connect Biopharma recently completed phase I evaluation of CBP-307 (66), reporting favorable results in single ascending and repeat dose arms that support progression to phase II.85 While the structure of this compound was not explicitly confirmed, the patent containing it was disclosed and it selects for a limited set of possible compounds of which 66 (R= F) is most thoroughly evaluated based on the data presented in the cited patent and is also the sole subject of separate process and crystal form patent

the OPTIMUM phase III study in RRMS patients, in which the compound is to be compared directly against teriflunomide.67 The second compound advancing from Actelion, cenerimod (53, ACT-334441), is being evaluated in a phase II study for the treatment of systemic lupus erythematosus (SLE).68 Receptos (acquired by Celgene) has been developing the direct-acting agonist ozanimod (54, RPC1063) for multiple indications.69,70 For RRMS, evaluation of ozanimod continued in the phase III SUNBEAM trial as well as in the phase III extension of the earlier phase II RADIANCE trial.69 For inflammatory bowel disease (IBD), ozanimod is progressing through a phase III trial in UC (TRUE NORTH trial) while the STEPSTONE phase II trial is ongoing in patients with Crohn’s disease.70 Ono Pharma progressed direct-acting ceralifimod (55, ONO-4641) through the DreaMS phase II trial in RRMS patients where the primary end point of reduction of cumulative number of MRI lesions was met.71 However, their marketing partner for this compound (Merck KGaA) pulled out of the agreement for further development, citing increased competition in the RRMS space.72 Subsequent progression of ceralifimod has not been reported. In 2015, Mitsubishi-Tanabe partnered with Biogen Idec on the development of the prodrug agonist amiselimod (56, MT-1303), with ongoing trials for several autoimmune disorders.73a The following year, Biogen-Idec dropped out of the licensing agreement, citing a changing competitive landscape.73b The structure of amiselimod is very close to that of fingolimod, differing only in the addition of a trifluoromethyl group on the phenyl ring (likely done to bring in selectivity against S1P3) and in the replacement of one methylene of the lipophilic alkyl tail with an oxygen atom. Phase II evaluation of amiselimod has been reported for RRMS, SLE, Crohn’s disease, and psoriasis.74 Etrasimod (58, APD334), a direct-acting agonist developed by Arena Pharma, was being evaluated in an ongoing phase II trial in UC patients.75 AbbVie (formerly Abbott) reported on the phase I development of ABT-413, an S1P1 agonist of undisclosed structure; however, recent pipeline updates have not included reference to this compound.76 Akaal Pharma is taking a unique approach in the S1P1 field for the development of its directacting S1P1 agonist AKP-11 (84, structure undisclosed) by focusing on topical application for the treatment of skin disorders.77,78 After disclosing favorable phase I results with 84 as a topical treatment for mild-to-moderate psoriasis, Akaal is progressing it into phase II evaluation for psoriasis and atopic 5277



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applications.86,87 Interestingly, this possible structure is virtually identical to one of the original direct-acting S1P1 agonists reported by Merck (Figure 5; 29), differing only in the addition of a fluorine on the phenyl ring adjacent to the polar headgroup. The advantage afforded by this modification over 29 was claimed to be a reduction in pharmacokinetic half-life (t1/2). In Sprague−Dawley rat, t1/2 was reduced from 11 h for 29 to 5.5 h for 66 (R = F) after oral administration and from 9 to 5.5 h after intravenous administration.87a It has not been reported as to what issues prevented the clinical advancement of 29 and related compounds, so it remains to be seen whether 66 can succeed where earlier close analogues did not.

from an acquisition of Praecis Pharma, was identified as a “clinical development candidate” and was prepared on a multikilogram scale. 9 8 , 9 9 Direct-acting compound GSK2263167 (77) was noted to be a potent and selective agonist of S1P1, with maximal activity in a mouse collagen induced arthritis model comparable to the activity observed with fingolimod.100a Furthermore, the synthetic development of a route capable of delivering kilogram quantities for “early development activities” is indicative of notable interest in this compound at one time.100b In a similar situation is naphthalene 79, from Novartis, for which a synthetic effort was described whose goal was the delivery of multikilogram quantities.101 Finally, Merck Serono described an in vitro and in vivo selection process leading to the identification of 78 as a clinical candidate.45 Notable in 78 is the disposition of the lipophilic and zwitterionic groups across the phenyl ring, which utilizes the less common meta rather than para orientation, a feature that brought in desired activity against S1P5 and improved efficacy in a mouse model for multiple sclerosis. (For other meta substitution patterns, see Figure 6; 34 and 35.)

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S1P1 AGONISTS: ADVANCED PRECLINICAL COMPOUNDS In addition to the compounds for which entry into clinical trials have been disclosed, a number of S1P1 agonists have been highlighted as late stage development prospects. In some cases, publications or presentations have suggested development status, while in other cases the attention afforded by their largescale preparation points to their status as molecules of interest. The path to clinical trial initiation is challenging, with late stage failures commonly sidelining otherwise compelling molecules, which could be the case with many of those presented here. However, given the resources devoted to their identification and progression, it is still worthwhile to take note of these compounds. Captured in Table 2, with structures shown in Figure 9, are compounds of this nature. All but two of the compounds are direct-acting agonists, with the majority falling into the category of polar-zwitterionic molecules. AbbVie reported on the synthesis of two closely related compounds, 67 and 68, with the goal of supporting clinical evaluation,88 while Actelion described the preparation of 69 on a 12 kg scale.89 Subsequently, a phototoxicity liability of 69 was discussed, indicating the likely reason for its lack of progression.90 Amgen has highlighted a series of agonists derived from a collaboration with Epix Pharma, culminating in the identification of AMG-369 (70), a polar-zwitterionic directacting agonist.91 70 and associated S1P1 assets were offered up for sale by Amgen in 2011, and no further development has been disclosed.92 Several advanced compounds have been disclosed from an isoxazole-based series of direct-acting agonists. Bristol-Myers Squibb reported the selection of BMS520 (71) as a development candidate and detailed an approach to its large scale preparation.93 In a separate disclosure, 72, built upon the same lipophilic framework, was characterized for in vitro and in vivo performance and was noted as under consideration as a development candidate.94 Introduction of a tricyclic constraint in this series led to 73, highlighted as progressing to further evaluation for suitability as a development candidate.95 In an initial report, Daiichi-Sankyo highlighted direct-acting zwitterionic compound CS-2100 (74) as a clinical candidate,96 although it was subsequently disclosed97 that 74 suffered from undesired enterobacterial intestinal metabolism of the oxadiazole ring that precluded further development. Given the prevalence of the oxadiazole ring in S1P1 agonists that have been advanced into late-stage development by multiple research teams, it is interesting that this finding has not been noted by others with structurally similar compounds. In addition to their confirmed clinical development compound, 64, GlaxoSmithKline has highlighted two other compounds with late stage interest. The pro-drug S1P1 agonist GSK1842799 (75), arising

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NEXT GENERATION OF SAFETY On the heels of early clinical reports of the side-effect profile of fingolimod, attention was soon drawn to activity on S1P3 as a culprit for some of the issues. In vivo studies in rodent with S1P3 sparing S1P1 agonists pointed to alleviation of pulmonary (bronchoconstriction) and cardiovascular (bradycardia) effects through deletion of activity on S1P3.39 These findings were consistent with observed CV safety improvement of nonselective S1P1/3 agonists when dosed in S1P3−/− mice as compared to when dosed in wild-type mice.102 Quite surprisingly, in the clinic, reduction of activity on S1P3 did not eliminate the undesired CV effects,29 with the sentiment of the field summed up succinctly in a quote from Novartis’ Gordon Francis that “The rodent lied.”103 It became clear that there were notable species distinctions with regard to the role of S1P1 vs S1P3 in cardiovascular signaling. Despite this disconnect, most research programs continued to focus on identifying S1P3-sparing molecules, as activity on S1P3 was believed to be dispensable in terms of maintaining the desired therapeutic effects but does carry potential liabilities. With the reduction or elimination of S1P3 agonist activity failing to offer a complete solution to the safety concerns of this class, research groups turned to the investigation of alternative strategies to mitigate the heart rate (HR) effects with clinical compounds and also to the development of new in vivo and in vitro methods to identify S1P1 agonists that offer the potential for enhanced clinical safety.

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MANAGING CLINICAL OBSERVATIONS THROUGH DOSING STRATEGIES As the earliest S1P3-sparing S1P1 agonists entered human clinical evaluation and were met with CV effects reminiscent of those elicited by the nonselective fingolimod, attention turned to utilizing dosing strategies to blunt the impact of the effects (for example to reduce the magnitude of the observed heart rate reduction). The CV effects were known to be transient, presumably due to eventual receptor downregulation on cardiac tissue. In line with this hypothesis, several groups have reported on dose up-titration strategies with the goal of gradually entering the desensitization phase without providing a strong initial CV signal. Naturally, this prolongs the time needed to 5278



Perspective

missed doses). This concern was investigated with ponesimod, wherein the transient HR reductions that were observed with a first dose of 20 mg but not a second daily dose were observed once again after a 7-day period of nondosing.104 This aspect was studied in much greater detail for siponimod, where after exploring multiple discontinuation periods, it was found that reinitiation without retitration could be safely done after a lapse in treatment of up to 96 h.110

achieve maximal desired pharmacology (e.g., targeted lymphocyte reduction). Actelion (Ponesimod, 52). In a phase I multiple ascending dose (MAD) study of ponesimod, up-titration was explored to reduce drug-related first-dose effects on sinus node automaticity and AV conduction.104 A dosing schedule of 10 mg daily for 4 days, 20 mg daily for 4 days, then 40 mg daily resulted in a reduced HR change as compared to initial single doses of either 20 or 50 mg. In a phase IIb trial of ponesimod in RRMS, a modified up-titration protocol was also employed.105 Three doses of ponesimod (10, 20, 40 mg) were evaluated, with all nonplacebo subjects starting on the low dose (10 mg) for 7 days, with escalation then to 20 mg for two-thirds of the subjects, and further escalation to 40 mg after an additional 7 days for half of that subgroup. HR reductions of approximately 10−12 beats per min (bpm) were noted on day 1 (with a 10 mg dose for all drug-treated subjects), but HR changes at the time of dose escalation to 20 and then 40 mg were nonsignificant as compared to the placebo group. Novartis (Fingolimod, 2). A comparison was made of a fixed dose of 1.25 mg versus an up-titration of fingolimod across 9 days (0.125 mg for 3 days followed by 0.25, 0.5, and 1.25 mg for 2 days each).106 The fixed dose regimen led to an average daily HR reduction of ∼8−11 bpm on the first 2 days before the HR gradually partially recovered. The up-titration cohort avoided the abrupt maximal HR change associated with the fixed dose, instead showing a gradual decline in HR of 1−2 bpm per day over 9 days, with the ending HR of the two treated groups showing very similar reduction as compared against the day 9 HR of the placebo group. Novartis (49). The difference in cardiovascular changes observed with Holter monitoring of subjects from a fixed dose regimen of 49 (2.0 mg/day over 21 days) was compared against two up-titration paradigms, each ending in 3−5 days at the 2.0 mg dose.107 In the first titration paradigm, the dose was stepped up with 4 days each at 0.3, 0.6, 0.9, and 1.2 mg before reaching the top dose of 2.0 mg for 5 days. In the second titration paradigm, 14 days at 0.5 mg was followed by 4 days at 1.2 mg prior to 3 days at 2.0 mg. Both titration regimens resulted in fewer recorded bradycardia events as compared to the fixed dose regimen. Novartis (Siponimod, 51). A CV safety comparison was made between a fixed dose of siponimod (10 mg/day) against two dose titration regimens that utilized an escalation from 0.25 to 10 mg over 9 or 10 days.108 While the first dose effect of 10 mg of siponimod was quite pronounced (a drop of 16 bpm at 2 h postdose), the dose titration arms saw no appreciable HR changes on day 1. As the study progressed, the HR of the dose titration groups saw a reduction of approximately 5 bpm as compared to placebo. Receptos (Ozanimod, 54). An up-titration procedure was incorporated into the phase II/III RADIANCE trial of ozanimod to attenuate first-dose cardiac effects.109 Drug-treated subjects were started on 0.25 mg for 4 days before escalating to 0.5 mg, from which point the participants either remained on 0.5 mg or were further escalated to 1.0 mg after an additional 3 days. While full details of the cardiovascular effects have not yet been reported, the rate reduction on day one at the 0.25 mg dose were very minor (2 bpm change compared to baseline). While up-titration approaches appear to have some utility in mitigating the CV effects elicited upon treatment initiation with S1P1 agonists, one logical concern would be how to manage patients after an intended or unintended drug holiday (e.g.,

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LOOKING BEYOND S1P3 SPARING AGONISTS FOR IMPROVED SAFETY In Vivo Approaches. While the surprising CV effects observed in humans with S1P3-sparing compounds highlights the potential pitfall of relying on animal models for prediction of human pharmacology, such models still may prove valuable for the selection of third-generation S1P1 agonists with improved safety profiles. The fact that rat and mouse differ from human in terms of CV response to S1P1 agonism prompted an evaluation of the response in other nonclinical species. It was reported that isolated atrial myocytes from guinea pig, but not from rat, responded to an S1P1 selective agonist by activating the specific ion channel (GIRK) linked to heart rate reductions.111 Extending from this observation, an in vivo telemeterized guinea pig model was developed for the characterization of ponesimod which was able to recapitulate some of the effects on heart rate and rhythm that were observed in the clinic.112 Furthermore, the guinea pig model was used to evaluate desensitization via up-titration, information that was translated to the clinical dosing regimen of ponesimod described above. In addition to the CV concerns, in vivo evaluation of undesired pulmonary effects of S1P modulators in nonclinical species has been reported from a number of research teams. While it is important to be mindful of the species-disconnect that was observed for the cardiovascular changes elicited by S1P agonists, the fact that preclinical pulmonary toxicity has been observed with S1P3-sparing compounds at least removes that receptor as a source of potential disconnect in regard to the prediction of pulmonary effects. Astellas monitored the increase in rat lung weights after administration of their compounds to avoid this undesirable side effect that had been observed with conventional S1P1 agonists.113 Compounds were administered for up to 7 days, with lung weights compared against body weight at the end of the evaluation and a change of greater than 10% indicating a positive result. Several compounds that were effective at inducing lymphopenia in rats (24 h ED50 0.10−0.35 mg/kg) were also shown to afford an increase in lung weight of less than 10% at a dose of 1 mg/kg, indicating some level of a desired therapeutic index (TI). In a very similar design, Receptos described a rat pulmonary toxicity evaluation in the identification of ozanimod.114 For a select group of compounds, a TI was generated by comparing the lymphopenia ED50 (the dose of each compound that enabled 50% reduction in lymphocytes 24 h after the last of 5 daily doses) to the dose producing a 10% increase in lung weight (lungs collected 24 h after the final dose in either 5-day or 14-day studies). While some compounds showed very poor results (TI of 1−2), others afforded a larger safety window (TI of 20−30). Ozanimod was among the tested set of compounds, providing a TI of 18 based on a 14-day evaluation. Rodent pulmonary toxicity evaluation was also reported to be part of the selection process for another clinical compound, 60.81,115 Originally prepared as a diastereomeric mixture of 5279



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Figure 10. Ex vivo rat trachea constriction assay for differentiation of S1P agonists.

reduction from 124% to just 24% constriction at the 10 μM concentrations. Full S1P receptor activity data is missing for this series, so it is not possible to discern if the change correlates with an improved selectivity profile of 81 and 83 (in particular, activity on S1P3) or reflects changes to other aspects of on-target or off-target activity. In Vitro Approaches. As our understanding of GPCR signaling has developed, it continues to be recognized as an increasingly complex process. Rather than functioning as simple “on/off” switches, GPCRs can exert a range of actions on multiple downstream pathways in response to particular receptor/ligand complexes.120 Selecting for specific ligandbiased signaling pathways has opened up new opportunities to dissociate beneficial effects from those that are detrimental or undesired.121 For example, this concept was exploited in the design of partial agonists of the nicotinic acid receptor (GPR109a) that maintained efficacy while reducing undesired flushing by selecting against β-arrestin activity in favor of Gi signaling.122 The selection process to identify the optimal receptor modulator profile requires the availability of appropriate in vitro assays to probe the signaling pathways, either directly or indirectly. Recent reports highlight the search for ligand-biased signaling among S1P1 agonists as a potential route to the identification of safer therapeutics from this field. As the S1P1 induced cardiovascular changes are believed to be due to activation of a G protein-coupled ion channel (GIRK), researchers at Meiji Seika Pharma sought to determine if such activation could be separated from the desired downregulation (functional antagonism), leading to lymphopenia.123 Compound optimization based on improved receptor internalization activity (a β-arrestin driven pathway) with reduced activity on Gi signaling pathways that presumably lead to GIRK activation (as assessed with a calcium flux assay) helped to identify CP-9531 (85, structure undisclosed).123−125 Furthermore, these researchers have disclosed a more detailed evaluation of S1P1 G protein signaling, with selection of compounds biased toward Gαi2 and Gαi3 signaling versus Gαi1, which is claimed as offering an improved cardiotoxicity profile.124 As 85 was recently outlicensed to Curadim Pharma for development, it is possible that the correlation of this in vitro profile to improved human safety will be investigated.125 The phosphate of clinical compound 60 (BMS-986104-P, 61) was described as demonstrating ligand-biased signaling as compared to the signaling of fingolimod-P.81 In either GTPγS or internalization assays, 61 proved to elicit a potent but partial agonist response, whereas in an ERK phosphorylation assay, a

eight isomers, 60 was selected from this set based on its ability to form the bioactive phosphate metabolite, in vivo potency in rodent lymphopenia models, and also based on performance in a mouse pulmonary toxicity assay. Mice were dosed with test compounds and 24 h, later an analysis was conducted to look for increased levels of protein in bronchoalveolar lavage (BAL) fluid obtained from the animals, which would be indicative of pulmonary vascular leak. While the 24 h ED50 for lymphopenia was found to be just 0.12 mg/kg, a dose 250-fold higher (30 mg/kg) led to no discernible negative pulmonary effects (as measured by protein levels from BAL fluid). The characterization of 84, the clinical compound from Akaal Pharma, included standard in vivo measures of efficacy (lymphocyte sequestration and activity in the mouse EAE model of multiple sclerosis) but also utilized an in vivo assay to monitor for changes to lung permeability.116,117 While the efficacy of 84 in mouse EAE was found to be comparable to that observed with fingolimod (1.3 mg/kg/day of 84 vs 1.0 mg/ kg/day of fingolimod), the level of lymphocyte reduction by 84 was markedly reduced in comparison to fingolimod after single doses or in mEAE treated animals. A comparison of lung permeability effects was conducted through the use of an Evans blue dye (EBD) extravasation evaluation. Administration of single doses of either 84 or fingolimod was followed 24 h later by EBD administration and subsequent lung fixation and visualization. While treatment with fingolimod increased permeability by 4-fold, the response to 84 was reduced to a 2-fold increase, indicating a potential improvement in pulmonary safety. Ex Vivo Approaches. A disclosure from Actelion highlights the utilization of an ex vivo model for the differentiation of a set of very closely related compounds on the basis of bronchoconstrictive response.118 This interest was perhaps spurred on by findings of dyspnea as a clinical side effect of Actelion’s lead compound ponesimod.119 Rings of trachea, which were excised from female Wistar rats, were suspended in tissue baths and their contraction was measured in response to exposure to test compounds. As shown in Figure 10, a very subtle modification to the pyridinyl substitution led to significant differences in constriction responses. Whereas isobutyl analogue 80 elicited a constriction response of 133% at 1 μM (percent relative to the level of constriction induced by 50 mM KCl), modification to the pent-3-yl group gave 81, which saw a reduced response even with a 10-fold increase in concentration (100% at 10 μM). Similarly, for matched pair 82 and 83, the isobutyl to pent-3-yl exchange resulted in a 5280



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emphasized for their activity at S1P1 (e.g., fingolimod) often carry potent S1P4 agonism as well, a clear beneficial or detrimental role has not been defined for this activity. The availability of selective agonists and antagonists (e.g., CYM50374 and CYM-50308; N-(4-(hydroxymethyl)-2,6-dimethylphenyl)-5-(3-methylthiophen-2-yl)furan-2-carboxamide and (2Z,5Z)-5-((1-(2,4-difluorophenyl)-2,5-dimethyl-1H-pyrrol-3yl)methylene)-2-((2-methoxyethyl)imino)-3-methylthiazolidin4-one) may help to clarify the role of this receptor.134 S1P5 Modulators. The efficacy of fingolimod and other S1P1 agonists in multiple sclerosis and preclinical models of that disease has been proposed to be due not only to the S1P1 induced lymphopenia, but also due to direct CNS effects from both S1P1 and S1P5 activation. Several recent disclosures highlight the development of agonists specif ic for S1P5 and point to their potential utility in CNS disorders such as MS.135 S1P Lyase. An alternative approach to disrupting the ability of lymphocytes to follow the S1P gradient as they egress out of lymph nodes and into circulation is to target not the cell surface receptor but the actual chemotaxis-inducing ligand, S1P. The gradient is maintained through careful production and elimination of S1P and its family members (see Figure 1). Inhibition of the S1P degrading enzyme S1P lyase, which is abundant in the lymphatic system, leads to an increase of S1P in that compartment.136 This normalization of the S1P levels leads to a reduction of circulating lymphocytes, pharmacology directly resembling that elicited by S1P1 agonists. Clinical exploration of this approach has been initiated with two inhibitors from Lexicon (LX2932 and LX2931; (1R,2S,3R)-1(2-(isoxazol-3-yl)-1H-imidazol-4-yl)butane-1,2,3,4-tetraol and (E)-1-(4-((1R,2S,3R)-1,2,3,4-tetrahydroxybutyl)-1H-imidazol2-yl)ethanone oxime).137 Sphingosine Kinase 1/2 (SK1/2). Another pathway opportunity is to target the phosphorylating enzymes that produce S1P from sphingosine (SK1 and SK2). A recent review of this area highlights the progress that has been made in identifying selective inhibitors of these kinases and the implications of inhibiting them in the context of human diseases.138 Anti-S1P Antibodies. Biologic approaches to modulation of the S1P pathway have also been explored with monoclonal antibodies designed to recognize and bind to S1P, thus reducing the pool of bioactive form of this lipid. LPath Incorporated progressed sonepcizumab into phase II trials for wet age-related macular degeneration and phase II trials for renal cell carcinoma.139 Unfortunately, the desired end points were not met in either trial.140

full agonist response (maximal stimulation) was obtained but with potency that was substantially weaker than that of fingolimod-P. The functional relevance of the bias displayed by 61 was explored in a separate in vitro assay, utilizing cultured human cardiomyocytes derived from inducible pluripotent stem cells. The use of a human derived cell line for the in vitro evaluation offered a means to bypass the established S1P receptor disconnect observed between rodent and human CV responses. A notable right shift in the response of 61, as compared to fingolimod-P, was hypothesized as being predictive of an improved human CV safety profile. Opportunities Beyond Agonists of S1P1. As the frontrunner of the sphingosine pathway targeted therapeutics, S1P1 agonists have garnered the most attention from industry and academia. However, antagonists of S1P1, modulators of the remaining receptors in the family, antibody approaches, as well as therapies aimed at related proteins in the sphingolipid pathway have seen significantly increased attention in recent years. While the scope of this article, and the large body of literature surrounding S1P1 agonists alone, precludes a more detailed discussion, it is worthwhile to briefly highlight some of the exciting work in those other areas. S1P1 Antagonists. As the primary pharmacology of S1P1 agonists (lymphopenia) is driven by functional antagonism of the receptor, it was reasonable to expect that the same result could be obtained with true antagonists of S1P1. Indeed, when compounds with sufficiently good PK properties were developed, antagonist-induced lymphopenia was observed.126 Subsequent efforts also detailed the efficacy of S1P1 antagonists in a variety of preclinical disease models including mouse EAE, mouse colitis, and for inhibition of tumor growth.127 Opportunities for structure-guided drug design within the S1P receptor field have been expanded with the recent availability of a crystal structure of S1P1.128 As this reported structure was of an antagonist bound to S1P1, the opportunity may perhaps be most impactful for this class. S1P2 Modulators. Standing as the lone S1P receptor family member not targeted by fingolimod-P, an understanding of the biological functions associated with S1P2 is continuing to be developed. This understanding has been aided by the identification of both agonists129 and antagonists130 for this receptor. One antagonist of S1P2 (ONO-1266, structure not disclosed) has reportedly entered clinical trials for portal hypertension.131 S1P3 Modulators. While most research programs have been aimed at avoiding S1P3 in favor of S1P1, there have been directed efforts toward identifying modulators specific to S1P3. In one report, both allosteric agonists (CYM-5541; N,Ndicyclohexyl-5-cyclopropyl-3-isoxazolecarboxamide) as well as bitopic antagonists (SPM-242; 2-amino-4-(2-chloro-4-((3hydroxyphenyl)thio)phenyl)-2-(hydroxymethyl)butyl dihydrogen phosphate) for S1P3 were described.132 Evaluation of a related bitopic S1P3 antagonist (SPM-354; (S)-2-amino-2-(2chloro-4-((3-hydroxyphenyl)thio)phenethyl)pentyl dihydrogen phosphate) in mouse models of cardiac function revealed a role for such antagonists in reversal of S1P induced heart block.133 As the translation of S1P receptor mediated CV effects from rodent to human was recognized to be poor, further studies will be needed to bridge the implications of this work to functions in higher species. S1P4 Modulators. With prominent expression restricted to hematopoietic tissue, S1P4 is a compelling protein to consider for therapeutic targeting. While S1P modulators that are

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CONCLUSION AND PERSPECTIVE A substantial medicinal chemistry investment, dependent upon in vivo driven SAR, led to the identification of fingolimod as the first, albeit inadvertent, synthetic agonist to be identified for the S1P receptors. Over the past 15 years, continued research aimed at understanding the sphingolipid signaling pathway has led to the generation of multiple compelling and druggable targets from this family. Premier among those targets is the S1P receptor subtype 1, agonism of which appears key to the efficacy of a marketed drug (fingolimod) and a target for which several late stage clinical compounds continue to be advanced. Agonists of S1P1 have demonstrated efficacy in numerous animal models of disease and their continued clinical testing in an increasing variety of disorders is clarifying the translatability of the preclinical data to human patients. The path has not 5281



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ABBREVIATIONS USED ALT, alanine transaminase; ATX, autotaxin; AV, atrioventricular; BBB, blood−brain barrier; bpm, beats per minute; cAMP, cyclic adenosine monophosphate; CNS, central nervous system; EAE, experimental autoimmune encephalomyelitis; Edg, endothelial differentiation gene; GIRK, G protein-gated inwardly rectifying potassium channel; GPCR, G proteincoupled receptor; GTPγS, guanosine-5′-O-[γ-thio]triphosphate; HDL, high-density lipoproteins; HR, heart rate; h, hour/hours; IP, intraperitoneal; IV, intravenous; LDL, lowdensity lipoproteins; PD, pharmacodynamic; PK, pharmacokinetic; PLL, peripheral lymphocyte lowering; PO, oral; sc, subcutaneous; S1P, sphingosine-1-phosphate; S1P1−5, sphingosine-1-phosphate receptors 1−5; SAR, structure−activity relationship; SK, sphingosine kinase; TI, therapeutic index; tox, toxicity; VLDL, very low-density lipoproteins

been without surprises, chief among which was the revelation that the cardiovascular responses under the control of S1P receptors show substantial species differences. The early decision by multiple research teams to drive away from activity on S1P3 to avoid bradycardia observed in humans, while not without merit, was ultimately not able to realize the full impact of clinical CV safety as was once hoped for. Nevertheless, clinical agents continue to navigate the balance between efficacy and safety, in some cases assisted by specific dosing paradigms. Multiple S1P agonists have now been evaluated with dose uptitration in order to manage the observed transient HR reductions associated with S1P1 agonists. Meanwhile, research teams are looking beyond receptor selectivity as a means to improve safety, with empirical in vivo models and prospective in vitro characterizations playing a role in the selection of thirdgeneration S1P1 agonists. The broader GPCR field in general has begun to embrace the search for ligands that demonstrate pathway bias in signaling as a means to dissociate desired from undesired activities. This concept has recently appeared in the hunt for S1P1 agonists, although it is too early to know if the ultimate clinical profile will match with expectations. The emergence of a crystal structure of S1P1 was certainly an important milestone in the field and, indeed, is still an infrequent occasion for GPCRs as compared to other drug target classes. In time, the translation of this structural information to a medicinal chemistry story is very likely to be reported. Thus, far, discovery efforts have predominantly relied on creative manipulation of pre-existing scaffolds, rational translation of chemical motifs (i.e., amino-phosphates to aminocarboxylates), and combination with high throughput screening results. Structural guidance, where reported, has been in the form of homology models, aided in some cases by mutagenesis. Although touched upon only briefly here, there have been many exciting advances in targeting the sphingolipid pathway outside of S1P1 agonists. The coming years will hopefully see expanded clinical evaluation of these targets and possibly the identification of further opportunities within this important family.

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REFERENCES

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AUTHOR INFORMATION

Corresponding Author

*Phone: 609-252-3593. E-mail: [email protected]. ORCID

Alaric J. Dyckman: 0000-0002-1050-2077 Notes

The author declares no competing financial interest. Biography Alaric J. Dyckman received his B.S. degree in Chemistry from California State University, Chico, before moving to Stanford University, where he obtained his Ph.D. in Organic Chemistry under the supervision of Prof. Paul Wender. In 2000, he joined Bristol-Myers Squibb as a medicinal chemist in the Immunoscience therapeutic area. During his time at BMS, he has worked on a variety of kinase targets, including p38α, where he contributed to the identification of multiple compounds that entered clinical trials. In addition, he has led programs directed towards both cell surface and intracellular receptor targets for the treatment of autoimmune disorders. As the Chemistry lead for the S1P1 agonist program, he oversaw the identification and advancement of several clinical development candidates. 5282



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