(IDO1) Inhibitors Based on a Phenylimidazole Scaffold

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Letter

Identification of Potent Indoleamine 2,3-Dioxygenase 1 (IDO1) Inhibitors Based on a Phenylimidazole Scaffold Michael Glenn Brant, Jake Goodwin-Tindall, Kurt Robert Stover, Paul Michael Stafford, Fan Wu, Autumn Rebekah Meek, Paolo Schiavini, Stephanie Wohnig, and Donald F. Weaver ACS Med. Chem. Lett., Just Accepted Manuscript • DOI: 10.1021/acsmedchemlett.7b00488 • Publication Date (Web): 11 Jan 2018 Downloaded from http://pubs.acs.org on January 11, 2018

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ACS Medicinal Chemistry Letters

Identification of Potent Indoleamine 2,3-Dioxygenase 1 (IDO1) Inhibitors Based on a Phenylimidazole Scaffold Michael G. Brant†, Jake Goodwin-Tindall†, Kurt R. Stover, Paul M. Stafford, Fan Wu, Autumn R. Meek, Paolo Schiavini, Stephanie Wohnig, and Donald F. Weaver‡,§,* Krembil Research Institute, University Health Network, 60 Leonard Avenue, Toronto, Canada, M5T 2S8 ‡ Department of Chemistry, University of Toronto, Toronto, Canada, M55 3H6 § Department of Medicine, University of Toronto, Toronto, Canada, M5G 2C4 Keywords: immunooncology, IDO1 inhibitors, structure-based drug design, molecular modeling

ABSTRACT: Inhibition of indoleamine 2,3-dioxygenase (IDO1) is an attractive immunotherapeutic approach for the treatment of a variety of cancers. Dysregulation of this enzyme has also been implicated in other disorders including Alzheimer’s disease and arthritis. Herein we report the structure-based design of two related series of molecules: N1-substituted 5-indoleimidazoles, and N1substituted 5-phenylimidazoles. The latter (and more potent) series was accessed through an unexpected rearrangement of an imine intermediate during a Van Leusen imidazole synthesis reaction. Evidence for the binding modes for both inhibitor series is supported by computational and structure-activity relationship studies.

Over the past two decades immunotherapy has emerged as a powerful tool in the treatment of many cancers.1 In this arena, IDO1 has received significant attention from both industry and academia.2-3 IDO1 is a heme-containing enzyme that catalyzes the oxidative cleavage of the C2-C3 indole double bond to produce N-formylkynurenine.4 The generated N-formylkynurenine is then further metabolized to other bioactive metabolites, including kynurenine, kynurenic acid, 3-hydroxy-kynurenine, quinolinic acid and eventually nicotinamide adenine dinucleotide (NAD+).2 Expression of IDO1 can be induced by IFN-γ, TNF-α and other inflammatory cytokines. Although initially identified as an important enzyme in modulating the immune response in placental tissue5, IDO1 was later implicated as a key mediator of innate and adaptive immunity in the microenvironment of tumors.6 The expression of IDO1 by various tumor cells leads to the depletion of tryptophan in the microenvironment and subsequent block of Tcell proliferation. Dysregulation of IDO1 expression has also been implicated in the progression of several other conditions such as inflammatory diseases, arthritis, and neurological disorders such as Alzheimer’s disease.7 Inhibition of IDO1 with a small molecule is an attractive immunotherapeutic strategy for the treatment of a wide range of cancers.8-9 Several IDO1 inhibitors are currently being evaluated in various stages of clinical trials as adjuvants or in some cases standalone therapies with traditional chemo- and

radiotherapies.10-12 To date various molecular scaffolds have been reported in the academic and patent literature that inhibit the activity of IDO1.3 1-Methyltryptophan (1-MT, 1, Figure 1) was the first reported inhibitor of IDO1 and is the N-methylated analog of tryptophan.13 Despite an inhibitory activity of 34 µM, 1-MT has shown efficacy in several phase II clinical trials for the treatment of solid tumors in combination with various antibody and small molecule chemotherapeutics.12 Epacadostat (2, Figure 1) has also shown promising efficacy and is currently being evaluated in phase II/III clinical trials.14

Figure 1. Representative IDO1 inhibitors The powerful combination of X-ray crystallography and molecular modeling has provided valuable insights for developing new IDO1 inhibitors. A number of co-crystals with IDO1 have been disclosed including PF-0684000315, 4-phenylimidazole4 (4-PI, 3) and members of the NLG-91916, hydroxylamidine17 and imidaz-

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othiazole18 inhibitor series. Based upon these X-ray bound cocrystals4, 18-19 the IDO1 active site is commonly divided into three regions: pocket A, pocket B, and a heme cofactor. Aromatic, halogen-substituted aromatics or heteroaromatic motifs (such as indole) are most frequently chosen to occupy pocket A.3 Pocket B contains a mixture of hydrophilic (Arg231) and hydrophobic (Phe226) residues (Figure 2). The heme cofactor contains two distinct structural features from a drug design perspective: the porphyrin-bound iron atom, and a propionate group which projects into the binding site. The mechanism of IDO1 proceeds through initial formation of a ternary complex (IDO1 Fe2+O2:tryptophan); following this Yeh et al. have suggested the presence of a ferryl (Fe4+) intermediate following oxidation of the indole C2-C3 double bond.20 Various functional groups that tightly bind to iron have been investigated to achieve potent (and in most cases, competitive) inhibition including 1,3-diazoles (4-PI, NLG-919)16, 21, imidazothiazoles18, triazoles22 and hydroxylamidines (epacadostat, 2)14. Additionally, many potent IDO1 inhibitors also form a hydrogen bond to the propionate of the heme. The X-ray bound structure of a fluorinated NLG-919 analog revealed that the hydroxyl group formed an extended hydrogen bond network with the heme propionate.16 Similarly, molecular modeling studies also revealed key interactions between the imidazothiazole18 series and the epacadostat23 series with the heme propionate. SAR studies conducted on the various literature inhibitors indicate that sufficient interaction with all three regions (pocket A, pocket B, and the heme) of the IDO1 active site is essential for potent (IC50 ≤ 100 nM) inhibition. However, despite the structural data that are available for IDO1, the development of novel IDO1 inhibitors in drug discovery remains a challenge.3

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tion was followed by a Stille coupling25-26 to attach a trityl protected imidazole ring. This was followed by protecting group removal to furnish the target molecule (6) in 50% yield overall from 4. Compound 6 was incubated with a standard reaction mixture consisting of human recombinant IDO1, potassium phosphate buffer (pH 6.5), L-tryptophan, ascorbic acid and methylene blue.3 The reaction was stopped by exposure to trichloroacetic acid and the initial product (N-formylkynurenine) hydrolyzed to form kynurenine. The formation of kynurenine was detected by treatment with p-dimethylaminobenzaldehyde to produce a yellow pigment, followed by measurement of UV absorbance (maximum 480 nm). Epacadostat 2 (experimental IC50 80.0 nM) was used as a reference compound (see supporting information for error estimates). The IC50 of 6 was determined to be 30.5 µM, comparable to the activity of 4-PI (IC50 = 48 µM)27. Despite the modest gain in potency of 6 versus 4-PI, compound 6 was evaluated as a suitably versatile scaffold for the generation of analogs.

Scheme 1. Synthesis of the 5-bromo-2-imidazoindole (6)

Reagents: (a) LDA, n-Bu3SnCl, THF, −78 °C; (b) Pd(PPh3)4, 4iodo-1-tritylimidazole, CsF, CuI, DMF; (c) K2CO3, MeOH, 60 °C; (d) AcOH, MeOH, 80 °C. To progress compound 6 our strategy focused on increasing potency through addition of suitable side-chains to occupy pocket B. Molecular modeling studies indicated an aromatic group bridged by an appropriate spacer (i.e. methylene) attached to the N1position of the imidazole would extend into pocket B. To test this hypothesis, compounds 9a-k were synthesized in two steps (one pot) using the Van Leusen imidazole synthesis protocol28 (Scheme 2). As such, imine formation between the appropriate benzyl amine and 2-indolecarboxaldeyde (7 or 8), followed by subsequent reaction with TosMIC / K2CO3 provided indoleimidazoles 9a-k (Scheme 2).

Scheme 2. Synthesis of indole-imidazoles 9a-k

Figure 2. Model of compound 6 in complex with IDO1 using crysal structure 4PK5. Our discovery effort focused on identifying inhibitors containing two previously explored structural motifs, and combining these motifs into a single scaffold. Specifically, we envisaged that a suitable lipophilic group such as a 5-bromoindole ring could occupy pocket A.24 Further, an imidazole group attached to the C2 position of the indole would bind Fe2+ through N3 and the free NH would potentially interact with Ser167 through hydrogen bonding. This was supported by computational modeling (using pdb:4PK5) which indicated that an imidazole attached to the C2 position of 5-bromoindole would be orientated at an appropriate vector to bind Fe2+ (Figure 2). As outlined in Scheme 1, 5-bromo2-imidazoindole (6) was synthesized in a 4-step sequence from compound 4. Stannylation of 4 (LDA, n-Bu3SnCl) at the C2 posi-

Reagents: (a) R1CH2NH2, DMF; (b) TosMIC, K2CO3, 60 °C. Compound 9a with a phenyl substituent linked by a methylene group has an IC50 of 13.6 µM: a fold increase in potency versus compound 6. Compounds were also tested in HEK293 cellular assays using a doxycycline inducable IDO1 cell line. Supernatant was collected and processed in accordance with the in vitro assay. Epacadostat (experimental EC50 = 8.74 nM) was used as a reference compound. The analogous nor-bromine compound 9b was found to be three-fold less active (IC50 = 34.8 µM). However,


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ACS Medicinal Chemistry Letters both compounds exhibited equivalent potency in cellular assay (EC50 11.0 and 10.8 µM respectively). We next investigated whether substituents in the para-position of 9a would increase potency by either interacting with Arg231 or by making hydrophobic interactions with additional residues in pocket B (Figure 2). Compounds 9c and 9e containing a 4-phenyl and 4trifluoromethyl substituent respectively, displayed poorer activity against IDO1, while the electron rich 4-methyoxyphenyl compound 9d displayed a modest potency increase compared to the parent 9a. Compound 9f with a 4-cyano substituent showed a 3fold increase in potency relative to 9a. Having identified the benzyl group of 9a as an N1-substituent capable of binding in pocket B (see supporting information), our next objective was to increase the potency of our inhibitor series by addition of a H-bond donor. We envisioned that inclusion of a H-bond donor would provide opportunity for interaction with the heme propionate group through hydrogen bonding. In particular, we were encouraged by the successful implementation of similar strategies in the NLG91916, imidazothiazole18, and hydroxyamidine14 inhibitor series (vide supra). Analogs 9g and 9h (both possessing hydrogen bond donors) were found to have negligible activity (>100 µM). However, installation of a hydrogen bond donor (amine or hydroxyl) at the ortho-position of 9a afforded differing effects on the inhibitory activity. While the 2-aminophenyl analog (9i) had reduced potency (50.6 µM), the 2-hydroxyphenyl derivative (9j) displayed an activity of 6.40 µM.

and the 5-bromoindole group now binding in pocket B. This flip in binding mode now orientates the indole-NH in proximity to hydrogen bond with the propionate of the heme. The phenol ring now occupies pocket A and the hydroxyl group acts as a hydrogen bond donor to Ser167 (Figure 3). Intermolecular base-induced imine tautomerizations have been previously reported.29-30 The formation of compound 10c can be mechanistically rationalized by tautomerization of intermediate 7i (potentially promoted by the 2-phenolate group) to produce 7ii (Scheme 3). Attempts to adjust the ratio of products, and obtain compound 10c as the exclusive product through increased stirring times, and varying the reaction temperature were ultimately unsuccessful. Using a new synthetic route as outlined in Scheme 4, we performed additional SAR studies on our new and more potent compounds (Series 2). The norhydroxyl analog 10b was found to be approximately five-fold less active than compound 10c. While the nor-hydroxyl / nor-bromo analog 10a displayed a 24-fold drop in potency. Based on precedent literature and our computational model, inclusion of substituents at the 5-position of the aromatic ring of 10c appeared optimal to occupy a small lipophilic cavity at the top of pocket A. Compounds 10d and 10e were synthesized containing 5-fluoro- and 5chloro substituents, respectively. Both analogs were found to be active in the nanomolar range.

Scheme 3. Mechanistic rationale for the formation of phenyl-imidazole 10c

Table 1. In Vitro Activity of Series 1

Entry

X

R1

IC50 (µM)

EC50 (µM)

9a

Br

Ph

13.6

11.0

9b

H

Ph

34.8

10.8

9c

Br

4-PhC6H5

34.2

3.09

9d

Br

4-MeOC6H5

21.6

4.29

9e

Br

4-F3CC6H5

>100

4.59

9f

Br

4-NCC6H5

3.81

6.92

9g

Br

2-piperidinyl

>100

10.7

9h

Br

(CHOH)Ph

19.7

9.47

9i

Br

2-H2NC6H5

50.6

12.0

9j

Br

2-HOC6H5

6.40

5.01

9k

Br

3-HOC6H5

1.60

9.97

The most potent of the series was found to be the 3-hydroxy substituted 9k with an activity of 1.60 µM. The modest changes in potency from the installation of the 4-cyano (9f) and 3-hydroxyl (9k) groups versus compound 9a were encouraging; however, of greatest interest was the isolation of a second, unexpected, byproduct from the Van Leusen reaction between 5-bromo-2indolecarboxaldeyde (7) and 2-hydroxybenzylamine. Upon close inspection of the reaction mixture, a second imidazole-containing compound was identified as a minor product (ca 2:1 ratio). After careful chromatographic separation, both products were analyzed using HSQC / HMBC spectroscopy (see supporting information). The structure of the minor product was assigned as 10c. While the major product of the reaction (9j) was found to have an activity of 6.40 µM, byproduct 10c was found to have an activity of 180 nM. Computational modeling of 10c supports a proposed binding mode with the 2-hydroxyphenyl group now binding in pocket A,

Compound 10d displayed an inhibitory activity of 100 nM while the chloro-compound 10e displayed an activity of 37.9 nM. To reduce lipophilicity and improve ligand lipophilicity efficiency (LLE), we investigated the possibility of switching to a 5fluoroindole ring.31-32 Compounds 10f-m were synthesized starting from known amine 12 as outlined in Scheme 4. Compounds 10f, 10l and 10m displayed comparable IDO1 IC50 values relative to their brominated analogs (10c, 10d and 10e respectively) as shown in Table 2.

Figure 3. Model of 10c in complex with IDO1 using crystal structure 4PK5.



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Table 2. SAR Studies of Series 2

Entry

X

R1

R2

R3

R4

R5

IDO1 IC50 (µM)

IDO1 EC50 (µM)

a

ClInt

cLogP

b

10a

H

H

H

H

H

H

4.44

9.12

0.3). Inhibitor 10m displayed the best LE value (0.44) which is comparable to the mean LE value (0.45) reported for oral drugs.34 Series 2 were then assayed for plasma (murine) protein binding which led to the identification of 10f (݂u,plasma = 4.49%) and 10l (݂u,plasma = 1.64%) as compounds with acceptable free fraction in plasma (݂u,plasma) and potency (see supporting information). In general, the fluorinated analogs displayed higher ݂u,plasma values, likely due to reduced lipophilicity relative to the brominated analogs (see supporting information).35 With these data in hand, we next decided to measure in vitro intrinsic clearance ClInt using mouse liver microsomes for series 2. Accordingly, compounds in series 2 were screened for mouse liver microsome stability. As expected, those compounds that exhibited higher ݂u,plasma also displayed higher ClInt. Efforts to reduce clearance and improve EC50 for this series are currently underway. In conclusion, we have described our approach towards two related series of IDO1 inhibitors, guided by rational-design and computational modeling. Our inhibitors represent promising, synthetically tractable leads for the future development of IDO1 inhibitors with tailored physicochemical properties.

ASSOCIATED CONTENT Supporting Information Supplementary figures, synthetic procedures, compound characterization, purification method of recombinant IDO1 protein, computational methods and biological assays. This material is available free of charge via the Internet at http://pubs.acs.org.

AUTHOR INFORMATION Corresponding Author


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ACS Medicinal Chemistry Letters * [email protected]

Author Contributions †

These authors contributed equally (M. G. B. and J. G-T.)

Funding Sources The authors thank the Krembil Foundation for financial support. D.F.W. thanks the Canada Research Chairs program for support as a Tier I CRC in Protein Misfolding Diseases.

ACKNOWLEDGMENTS We thank Dr. Christopher J. Barden and Dr. Mark A. Reed for helpful discussions. We thank Dr. Sergiy Nokhrin for assistance with NMR spectroscopy.

ABBREVIATIONS IDO1, indoleamine 2,3-dioxygenase 1; TDO2, tryptophan 2,3dioxygenase; IFN-γ, interferon-γ; TNF-α, tumor necrosis factorα; 4-PI, 4-phenylimidazole; SAR, structure-activity relationship; TosMIC, tosylmethyl isocyanide; Boc, tertbutoxycarbonyl; LDA, lithium diisopropylamide; THF, tetrahydrofuran; DMF, N,N-dimethylformamide; LE, ligand efficiency; LLE, ligand lipophilicity efficiency; Ar, aryl group; IC50, median inhibition concentration (concentration that reduces the effect by 50%); EC50, median effective concentration (concentration that induces a 50% effect in a functional in vitro assay).

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