New Potent Antibacterial Oxazolidinone (MRX-I) with an Improved

Drug Annotation pubs.acs.org/jmc

New Potent Antibacterial Oxazolidinone (MRX-I) with an Improved Class Safety Profile Mikhail F. Gordeev* and Zhengyu Y. Yuan MicuRx Pharmaceuticals Inc., Hayward, California 94545, United States ABSTRACT: Oxazolidinones comprise an important class of antibacterial protein synthesis inhibitors. Myelosuppression and monoamine oxidase inhibition (MAOI) are key independent causes for limiting adverse effects in therapy with the sole approved drug of this class, linezolid. This annotation describes a novel oxazolidinone agent, (S)-5((isoxazol-3-ylamino)methyl)-3-(2,3,5-trifluoro-4-(4-oxo-3,4dihydropyridin-1(2H)-yl)phenyl)oxazolidin-2-one (MRX-I), distinguished by its high activity against Gram-positive pathogens coupled with markedly reduced potential for myelosuppression and MAOI. The medical need, medicinal chemistry rationale, preclinical data, and phase I clinical trial summary for this new agent are reviewed herein.

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first representative drug linezolid (Zyvox) in 2000.5 Linezolid is highly active against all major Gram-positive pathogens, including multidrug resistant (MDR) staphylococci, enterococci, streptococci, as well as mycobacterial species. To date, linezolid remains the sole approved antibacterial of the oxazolidinone class of protein synthesis inhibitors. The drug is distinguished by unique binding at a distinct region of 23S RNA adjacent to the peptidyl transferase center of the 50S ribosomal subunit.6 This novel site of action accounts for a remarkable lack of cross-resistance between linezolid and other antibacterials, including essentially all therapeutic protein synthesis inhibitors. An extremely low propensity toward developing bacterial resistance to linezolid in all target pathogens is apparent from both historic and the most recent surveillance data.7 The latter indicates virtually no significant resistance to linezolid after nearly 14 years of its clinical use. This feature is of paramount importance due to the widespread emergence of multidrug-resistant (MDR) microorganisms in both hospitals and the community.6,8 The antibacterial coverage of linezolid, coupled with excellent oral bioavailability, accounts for its important role in the treatment of serious Gram-positive infections and for the drug’s blockbuster status among anti-infectives.

INTRODUCTION In spite of massive scientific and financial investment into preclinical and clinical evaluation of pharmaceuticals, there is an inherent risk that the drug safety may not be fully elucidated in the research and development process. This issue cuts across therapeutic fields and pharmaceutical classes, as illustrated by postmarketing reports of serious adverse effects and call for drugs withdrawal, including examples of antibacterial protein synthesis inhibitors chloramphenicol1 and telithromycin.2 Outside of the anti-infective arena, the COX-2 inhibitor rofecoxib was withdrawn in 2004,3 prompting a Food and Drug Administration (FDA) review of this drug class at large and warnings for related agents. These and other examples provide ample evidence of the need for extensive drug safety evaluation, presently extended into postmarketing surveillance, including the FDA Sentinel Initiative,4 for adverse effects reporting. As a separate, if related issue, this recent history illuminates the critical importance of selecting an optimal strategy toward next-generation pharmaceuticals, necessitating close attention to key limitations for each pharmaceutical class, as required for the critical balance of potency and safety. While it is impossible to forecast all adverse effects that may manifest in a large patient population only post-approval, a case could be made for known class toxicities to be tackled in early phases of research. Thus, the quest for new agents with enhanced biological activity must be weighed against the elevated risk of adverse effects. This consideration is of particular importance if the drug’s intended activity and its mode of action are fundamentally associated with biochemical mechanisms responsible for a potential toxicity in human. Herein, we report progress toward addressing this issue for a class of oxazolidinone antibacterial agents acting via inhibition of protein synthesis in bacteria, with a similar mechanism ascribed to the inhibition of mitochondrial protein synthesis in humans. The oxazolidinone class of antibacterial protein synthesis inhibitors has attained prominence since the introduction of its © XXXX American Chemical Society

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ANTIBACTERIAL OXAZOLIDINONES: CLASS SAFETY LIMITATIONS AND THE MEDICAL NEED

Despite its undisputed commercial success, linezolid is subject to serious safety limitations, as reviewed by Vinh and Rubinstein.9 Primary safety concerns center on myelosuppression and MAOI, which have been recognized as two independent phenomena associated with key adverse effects in linezolid therapy. Received: December 17, 2013

A

dx.doi.org/10.1021/jm401931e | J. Med. Chem. XXXX, XXX, XXX−XXX

Journal of Medicinal Chemistry

Drug Annotation

term therapy is succeeding in clinical trials of acute bacterial skin and skin structure infections, with apparent amelioration of the intrinsic myelosuppressive potential of tedizolid due to a truncated dosing regimen and the generally reversible nature of myelosuppression, with normalized platelet counts reported 5− 6 days post-therapy.21 While no tedizolid binding to mitochondria was detected,22 it remains to be established whether it is safe in expanded patient populations, especially if a longer treatment is required such as seen with off-label or compassionate linezolid therapy. This will be conclusively determined only after the anticipated regulatory approval of tedizolid and the wide introduction of this promising new agent into hospital formularies. To the best of our knowledge, no other work has described efforts directly targeting a safer oxazolidinone antibacterial. Ideally, the next-generation drug of this class would maintain high levels of antibacterial activity in vitro and in vivo while exhibiting a superior (vs linezolid) safety profile. Such an agent should offer a significantly reduced propensity for myelosuppression as well as for MAOI to reduce the adverse effects potential and thereby permit the longer-term therapy required for hard-to-treat Gram-positive infections, such as diabetic foot infection and osteomyelitis. Herein, we review the preclinical and early clinical progress toward identification of a novel oxazolidinone agent that maintains high antibacterial activity while potentially addressing some of the key toxicity issues associated with linezolid therapy.23 With aforementioned class limitations in mind, our research strategy specifically targeted improving the oxazolidinone safety profile rather than merely enhancing the antibacterial potency of a new agent.

Myelosuppression, also referred to as bone marrow toxicity, is the chief therapy-limiting effect of the drug.9 Importantly, myelosuppression is directly associated with the inhibitory mode of action of linezolid, likely due to a homology between the 23S RNA target in prokaryotes and genetically related mitochondrial protein synthesis machinery in mammals.10 While early clinical data suggested relatively low incidence of myelosuppression, several later reports (see a review9 and references therein) revealed an elevated incidence of myelosuppression-associated effects, including thromobocytopenia, leukopenia, pancytopenia, and anemia. Attassi11 reported a thrombocytopenia incidence of 32% after over 10 days of the linezolid therapy. While the myelosuppressive effects are generally reversible, occurrences of optical neuropathy12 with rare but irreversible vision impairments13 likewise have been ascribed to the mitochondrial toxicity during extended linezolid therapy. Myelosuppression is believed to be generally infrequent in the linezolid treatment of duration ≤14 days, but this issue has prompted a black box warning in the drug’s prescription information.14 This concern limits the approved duration of linezolid therapy to 14 days, with an exception of 28 days made for use against serious infections due to vancomycinresistant enterococci (VRE). Furthermore, a complete blood count analysis is mandated for linezolid therapy with duration over 14 days.14 Historical efforts toward a safer oxazolidinone agent targeting long-term therapy are illustrated by the agent PF-03315011, a compound that originated at Vicuron15 and was advanced into development by Pfizer.16 Huband17 described the improved selectivity of this compound, including its attenuated myelosuppression and MAOI compared to linezolid. No subsequent clinical progression of this agent has been reported. Furthermore, no intrinsically (either at the target or cellular level) safer drug candidates of this class have entered clinical trials, even as recent expert opinions reveal that a standard linezolid regimen may be insufficient in certain patient populations.18 The drug’s dosing directly relates to its myelosuppressive potential, which limits the approved therapeutic dose and safe in vivo exposure for linezolid. Separately, MAOI of linezolid is associated with its potential for drug−drug interactions as well as central nervous system and blood pressure effects.19 Dietary limitations on ingestion of common thyramine-containing foods are required. While the toxicity due to MAOI is arguably not as serious as myelosuppression, it is still a concern for linezolid therapy, as reflected in the drug’s prescribing information. This consideration is of particular importance due to the fast onset of MAOI toxicity when a patient requires a serotonergic drug therapy concomitant to the administration of linezolid.19 The majority of recent efforts in the antibacterial oxazolidinone field are aimed at enhancing the potency of new compounds rather than addressing class safety issues. Some examples include clinical and investigational agents tedizolid, radezolid, posizolid, and LCB01-0371 (as reviewed by Pucci and Bush8). Thus, recent clinical trials of tedizolid phosphate (TR-701, a phosphate prodrug of the active moiety TR-700)20 by the Trius group explored an opportunity for an optimized therapeutic index through enhanced in vitro and in vivo activity of the agent. This is achieved via a once-daily tedizolid dosing of 200 mg/day (in contrast to the twice-daily linezolid dose of 2 × 600 mg) and with a shortened treatment duration compared to linezolid, possibly limited by the time frame of hematopoietic and blood cells’ life cycles. This short-

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MEDICINAL CHEMISTRY TOWARD THE DESIGN AND IDENTIFICATION OF THE NEW CLINICAL OXAZOLIDINONE The antibacterial oxazolidinone class presents a paradoxical challenge for medicinal chemists due to unique structure− activity relationship (SAR) restrictions. Many researchers have been lured into the oxazolidinone field by the apparent ease of synthesizing “new active compounds”, largely due to the relatively flexible SAR vis-à-vis the left-side C-ring structure (the Pharmacia and Upjohn substructure designation,24 as illustrated in Figure 1, is used herein). Since the pioneering

Figure 1. Linezolid and the new clinical agent, (S)-5-((isoxazol-3ylamino)methyl)-3-(2,3,5-trifluoro-4-(4-oxo-3,4-dihydropyridin1(2H)-yl)phenyl)oxazolidin-2-one.23a

discovery of antibacterial oxazolidinones by the Du Pont Merck Pharmaceutical Co.,25 most global pharmaceutical companies and many other groups have been involved in this research area. However, most of the new molecules offered no potential for clinical advantage over linezolid, with the majority of the active analogues found to be significantly more toxic than this drug,26 as illustrated by a negligible number of clinical investigational oxazolidinones, obviously disproportional to the multitude of B



Drug Annotation

toward the inherent class effects of MAOI and myelosuppression, with the latter often observed for cytotoxic structures31 such as conjugated and planar biaryl derivatives. This structural differentiation between linezolid and its trifluoro analogue was noted by Barbachyn30 despite the absence of an explicit correlation with improved MAO safety. Among several C-ring classes evaluated in our work, new analogues of known highly potent structures featuring a pyridine C-ring were included as well as a series of novel compounds incorporating the dihydropyridone C-ring. Notably, any ortho-substututed structures were deliberately excluded from these two series in a prior research by the Dong-A and Vicuron−Pfizer groups, respectively.27 The bis-heteroaryl Cring series originated at Dong-A has subsequently yielded the clinical candidate tedizolid.20b The novel ortho-fluorophenyl oxazolidinones discussed herein were prepared by modifications of chemistry previously described for des-ortho-fluoro progenitors, as illustrated in Scheme 1 (additional syntheses and specific examples are detailed in ref 32). To identify whether a select class of ortho-fluorophenyl oxazolidinones displayed appreciable antibacterial potency, a primary in vitro assessment initially was performed against a panel of Gram-positive bacterial strains including S. aureus. As illustrated in Table 1, respective pairs of compound 1 and 2 either lacking or incorporating the ortho-fluoro substituent have been compared to assess SAR effects of this structure variation. As anticipated, our initial results have followed the established SAR trend, with about a 4-fold drop in the antimicrobial potency for ortho-fluoro compounds 2b−2d when compared to the respective des-ortho-fluoro progenitors 1b− 1d, as illustrated by the data in Table 1 (representative literature data from Park25 are included therein as compounds 1a and 2a). However, the compounds featuring the dihydropyridone C-ring suffered only about 2-fold decline in potency against S. aureus, with MIC values of 0.5 and 1 μg/mL for oxazolidinones 1e and 2e, respectively (Table 1). It may be reasoned that the dihydropyridone heterocycle bears a general resemblance to the morpholine C-ring featured in linezolid and, by extension, to the aforementioned trifluorophenyl analogue of linezolid of Barbachyn.29 In addition, the relatively more planar (vs the morpholine heterocycle) dihydropyridone C-ring likely contributes to an increased antibacterial activity of the respective oxazolidinones vs linezolid, while the increased polar surface area of the dihydropyridone structure may partially compensate for a more lipophilic di- or trifluorinated B-ring, as compared to the nondihydropyridone examples of Table 1. This encouraging result has prompted an optimization round with a focus on the dihydropyridone C-ring derivatives incorporating up to three fluorine atoms in the phenyl B-ring structure. In vitro tests included antibacterial potency and MAOI evaluation, as well as in vivo efficacy determination in the S. aureus mouse septicemia model (Table 2). As illustrated by the data of Table 2, the ortho-fluoro substitution was reasonably well tolerated across several dihydropyridone-containing structures including both di- and trifluoro derivatives. Interestingly, difluorophenyl derivatives were generally more potent than respective trifluorophenyl analogues, as illustrated by MIC values of 1 and 2 μg/mL for compounds 2e and 3, respectively. However, in spite of the high potency (similar to that of linezolid), these compounds displayed oral efficacy inferior to the drug in the mouse infection model (Table 2).

research and patent publications on the topic. As noted by Renslo26b in 2010, “A highly potent and...selective oxazolidinone is...the ideal choice, but no such analogue has yet been disclosed...”. Despite the relatively simple oxazolidinone structure, linezolid remains the only approved drug of the class nearly 14 years since its clinical introduction. Importantly, SAR modifications at structural sites other than the C-ring structural have proven to be far more restrictive, limiting opportunities to derive a selective antibacterial molecule. Thus, in a seminal publication, Park25 ascertained critical SAR limitations governing substitutions in the aromatic B-ring. Specifically, substitutions in a position 2 (i.e., ortho in relation to the oxazolidinine ring) were deemed prohibited: “The 2-substituted compounds have, at best, weak activity”, and “... 2,4,6-trisubstituted derivatives are devoid of antibacterial activity”. Notably, examples by Park included 2-fluorophenyl analogues, likewise found inactive. This SAR restriction was further restated by other groups (see, for example, a review by Ford5a). Subsequently, the vast majority of later studies avoided the disfavored structures, as apparent from multiple publications explicitly limiting any aromatic ortho-substituents to the sole hydrogen atom (see, for example, representative patent publications27 and SAR reviews26a,28). In 2005, Barbachyn29 described a set of new oxazolidinones incorporating the 2,4,6-trifluorophenyl B-ring. In a remarkable deviation from the classical SAR, the new examples maintained good antibacterial activity, with only marginal reduction in activity compared to des-ortho-fluoro B-ring progenitors. Thus, a Staphylococccus aureus MIC90 (minimum concentration to inhibit the growth of 90% strains tested) of 8 μg/mL was determined for trifluorophenyl linezolid analogue (PF00987296), a value close to the MIC90 of 4 μg/mL for the comparator linezolid. Notably, the new compound was also reported to display a reduced MAO-A inhibition compared to linezolid.29 The unique nature of this observation is apparent from the narrow set of closely related structures described. Indeed, all examples therein featured the acetamidomethyl C-5 group in combination with a few saturated six-member heterocycles including morpholine, piperazine, tetrahydropyran, and tetrahydrothiopyran C-rings (Figure 2).

Figure 2. General structures for trifluorophenyl oxazolidinones of Barbachyn29 and the advanced lead30 of this series.

The limited scope of this discovery is in line with the established SAR, effectively making this an exception from the general restriction for ortho substitutions in the aromatic B-ring. Inspired by this intriguing SAR observation, our group has embarked on extensive exploration of novel ortho-fluorophenyl oxazolidinones in the hope of arriving at other unique structures that might combine the desired antibacterial potency and attenuated MAOI potential. We rationalized that a distinctly nonplanar A- and B-rings disposition forced by the ortho-fluoro substituent may allow for differentiation of such structures from the classical oxazolidinones in their propensity C



Drug Annotation

Scheme 1. Representative Synthesis of Dihydropyridone Oxazolidinones Derivatives: The First Preparation of the New Clinical Agenta

Reagents and conditions: (i) piperidine-4-one hydrochloride, DIEA, NMP, −5 °C to rt, 90%; (ii) trimethylsilyl triflate, TEA, THF, 0 °C to rt, 98%; (iii) allyl methyl carbonate, Pd(OAc)2, DMSO, 60 °C, 95%; (iv) Fe, NH4Cl, aq EtOH, 100 °C, 95%; (v) isobutyl chloroformate, Py, DCM, 0 °C to rt, 82%; (vi) (R)-oxiran-2-ylmethyl butyrate, LiOBu-t, THF, MeCN, 0 °C to rt, 74%; (vii) MsCl, TEA, DCM, rt, 90%; (viii) tert-butyl isoxazole-3ylcarbamate, KOBu-t, DMF, rt, 75%; (ix) aq HCl, EtOH, EtOAc, rt, 80% a

preclinical and clinical evaluation (the original reports preceding this perspective are cited in ref 23).

To improve in vivo activity, a survey of additional C-5 group analogues incorporating amide, carbamate, triazole, isoxazole ether, and isoxazole amine derivatives was performed. This resulted in the identification of compounds with efficacy similar or even superior to that of linezolid, such as compounds 4, 5, and 7 (Table 2). Importantly, the new ortho-fluoro dihydropyridone series represented by compounds of Table 2 exhibited significantly reduced MAOI compared to linezolid. Surprisingly, some compounds displayed MAOI attenuated over 20-fold as compared to the corresponding des-ortho-fluoro analog (for example, IC50 >100 μg/mL for compounds 2e and 5). This dramatic effect was not anticipated based on the prior data of Barbachyn, wherein the trifluorophenyl analogue of linezolid exhibited about 5-fold reduced MAOI compared to the reference drug.29 The compound 7, (S)-5-((isoxazol-3ylamino)methyl)-3-(2,3,5-trifluoro-4-(4-oxo-3,4-dihydropyridin-1(2H)-yl)phenyl)oxazolidin-2-one (MRX-I), was selected for further evaluation. A separate testing has revealed that the aforementioned lead exhibits distinctly attenuated over linezolid cytotoxicity in the human bone marrow CD34+ test, an assay that has been reported to be predictive of the myelosuppressive toxicity of oxazolidinones.34 Thus, the bone marrow CD34+ inhibition for compound 7 compared to linezolid and the clinical oxazolidinone tedizolid indicated a distinctly reduced toxicity for the new agent compared to linezolid, with even more pronounced differentiation from tedizolid, the active form of its phosphate prodrug (TR-701)20b (Table 3). Admittedly, the intrinsic bone marrow cytotoxicity of an oxazolidinone agent may not always manifest in vivo or reveal itself in every patient population. The tedizolid therapy was well tolerated in a phase III trial, even if with a 6-fold reduced daily dosing and ca. 2-fold shorter treatment regimen (from 14 to 6 days) compared to linezolid. The high anti-MRSA potency of compound 7, along with its reduced toxicities in bone marrow CD34+ and MAOI assays, have prompted the advance of this candidate into further

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PRECLINICAL PROFILE OF COMPOUND 7: MICROBIOLOGY The clinical compound 7 is highly potent against all Grampositive clinical isolates of staphylococci, streptococci, and enterococci, including MDR organisms such as MRSA, methicilline-resistant Streptococcus epidermidis (MRSE), penicillin-resistant Streptococci (PRSP), and VRE (as originally reported by Zhu23a). Antibacterial activity of compound 7 against Gram-positive pathogens is generally comparable to that for linezolid, as illustrated in Tables 4−6. Similar to linezolid, the new agent is inactive against Gram-negative bacteria. Significantly, the potency of the new agent against MRSA in the agar dilution assay was 2-fold higher than that of linezolid: MIC90 values were 0.5 and 1 μg/mL for compound 7 and the comparator drug, respectively (Table 4). Similar to linezolid, the new agent exhibits high activity against multiple strains of enterococci and streptococci species (Tables 5 and 6). Similar to the comparator drug, compound 7 displays bacteriostatic activity against enterococci. The agent exhibits bactericidal activity against Streptococcus pneumoniae, and modest bactericidal activity against some S. aureus and Streptococcus pyogenes strains. The new agent exhibited a significant postantibiotic effect (PAE) against S. aureus and S. pneumoniae: 1.6 and 1.8 h, respectively. These results are comparable to the PAE for linezolid.23a As typical for the class, the compound 7 exhibits an extremely low resistance potential with respect to both spontaneous and multistep selection resistance (as originally reported by Huang23b). In line with the oxazolidinone mode of action, bacterial strains resistant to linezolid are cross-resistant to the new agent, with an MIC >16 μg/mL against the clinical isolate S. aureus 4184 for both compound 7 and the comparator D



Drug Annotation

Table 1. Representative SAR towards Selection of the Dihydropyridone Oxazolidinone Series with orthoFluorophenyl Substitutions: Related Compounds 1 and 2 Are Compared

Table 2. B-Ring and C-5 Group SAR for Preliminary Selection of the Clinical Compound 7: Potency, MAOI, and Efficacy in the Mouse S. aureus Septicemia Model

a

MIC against MRSA strain SAU1009. bMAO-A inhibition assay of ref 33. Values in parentheses are for linezolid control. cEfficacy in murine S. aureus septicemia model with oral drug administration. Values in parentheses are for linezolid control. dA comparator compound of ref 27a. eLinezolid.

Table 3. In Vitro MAOI and Human CD34+ Bone Marrow Cells Growth Inhibition for Compound 7 Compared to Linezolid and Tedizolid Controls

a

Minimum inhibitory concentration (MIC) against methicillinresistant S. aureus (MRSA) strain SAU1009, except for the literature data25 for compounds 1a and 2a. bReported MIC data for compounds from ref 25. cCompared to self.

drug. Similar to linezolid, the new agent exhibits an extremely low frequency of spontaneous resistance, with values in S. aureus of 128 32

Number of bacterial strains tested are given in parentheses. PISP: penicillin intermediate-sensitive S. pneumoniae. PSSP: penicillinsensitive S. pneumoniae.

Table 7. Slow MIC Creep in a Serial Passaging Study for Compound 7 and Linezolid serial passage no.

compound 7 MIC (μg/mL)

linezolid MIC (μg/mL)

parent P1 P2 P3 P4 P5 P6 P7 P8 P9 P10

2 2 2 2 2 2 2 2 2 2 4

2 2 2 2 2 2 4 4 4 4 4

similar to that of linezolid in localized tissue infections caused by S. aureus isolates. Thus, across a broad range of animal infection models, the oral efficacy for compound 7 was comparable to that of linezolid against multiple Gram-positive bacterial strains.

1 >128 128

a

Number of bacterial strains tested are given in parentheses. VAN-S: vancomycin-sensitive.

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PRECLINICAL PROFILE OF COMPOUND 7: PHARMACOKINETICS (PK) Oral absorption of compound 7 occurred rapidly in mouse, rat, and dog, with peak plasma concentrations observed at 0.5−2.6 h postdose (as originally reported by Chen;23d Table 11). In mouse, rat, and dog, respectively, PK parameters were determined as follows: dose-normalized Cmax/dose was 524, 1065, and 259 ng/mL/(mg/kg); dose-normalized AUC0−t/ dose was 1654, 3703, and 1664 ng·h/mL/(mg/kg); T1/2 was 1,

Likewise, the new agent displayed high efficacy in animal models of localized bacterial infections, as illustrated by data for MSSA and MRSA mouse thigh infection models (Tables 9 and 10). The new agent exhibited a dose-dependent antibacterial effect in thigh infections caused by staphylococci isolates, with an excellent pathogen eradication of 2.45−4.53 units for MRSA infection in neutropenic rodent (Table 10). Its efficacy was F



Drug Annotation

Table 8. Efficacy of Compound 7 in Mouse Systemic Infection Models compound 7

linezolid

organism

MIC (μg/mL)

ED50 (range) (mg/kg)

MIC (μg/mL)

ED50 (range) (mg/kg)

S. aureus ATCC 29213 (MSSA) S. aureus 0612 (MRSA) S. aureus 0605 (MRSA) S. aureus 15 (MSSA) S. pneumoniae ATCC 49619 (PISP) S. pneumoniae 0806 (PSSP) S. pneumoniae 0613 (PRSP) E. faecalis ATCC 29212 (VSE) E. faecalis EFL 4041 (VRE) E. faecalis HH22 (VSE, HLGR) S. pyogenes 556

1 2 2 2 1 2 2 1 1 2 1

8.0 (5.2−12.3) 7.2 (5.2−10.0) 12.0 (8.4−17.1) 5.7 (4.2−7.9) 8.1 (6.1−10.7) 22.0 (18.4−26.3) 10.5 (7.8−14.0) 14.1 (6.9−28.7) 6.2 (4.8−7.9) 7.4 (6.0−9.2) 8.9 (6.9−11.4)

1 2 2 2 1 2 2 1 1 2 1

9.0 (7.1−11.5) 8.7 (6.3−11.8) 10.2 (7.8−13.3) 5.9 (4.6−7.5) 8.17 (6.5−10.3) 16.8 (14.7−19.1) 9.3 (7.1−12.3) 13.4 (9.3−19.5) 6.0 (4.7−7.5) 5.6 (4.0−7.9) 7.8 (6.0−10.1)

Table 9. Efficacy of Compound 7 in S. aureus ATCC29213 (MSSA) Mouse Thigh Infection Model: Colony-Forming Units (CFU) Reduction Post-Treatment, 10 Animals Per Dosing Group compound 7 (MIC 1 μg/mL) dose (mg/kg) 5 10 20 40 80

linezolid (MIC 1 μg/mL)

LogCFU/thigh

ΔLogCFU/thigh

± ± ± ± ±

0.95 3.29 3.33 3.42 3.73

7.19 4.85 4.81 4.72 4.41

0.66 0.94 1.13 0.78 0.43

LogCFU/thigh

ΔLogCFU/thigh

± ± ± ± ±

1.05 2.69 2.82 3.64 3.70

7.09 5.45 5.32 4.50 4.44

1.46 1.37 1.39 0.47 1.27

Table 10. Efficacy of Compound 7 in S. aureus 0605 (MRSA) mouse thigh infection model: CFU reduction post-treatment, 10 animals per dosing group compound 7 (MIC 2 μg/mL) dose mg/kg 5 10 20 40 80

linezolid (MIC 2 μg/mL)

LogCFU/thigh

ΔLogCFU/thigh

± ± ± ± ±

2.45 2.47 3.60 4.13 4.53

5.61 5.59 4.46 3.93 3.53

1.68 1.70 1.44 0.62 0.75

5 (oral)

15 (oral)

45 (oral)

5 (iv)

gender M F average M F average M F average M F average

Tmax (h)

Cmax (μg/mL)

T1/2 (h)

AUC0−t (μg·h/mL)

0.50 0.67 0.58 1.00 1.17 1.08 1.00 1.67 1.33

4.60 9.39 7.00 10.71 17.23 13.97 27.82 49.99 38.91

1.08 2.07 1.57 1.18 1.47 1.32 1.07 1.87 1.47 0.99 1.51 1.25

10.16 31.47 20.81 34.31 64.71 49.51 93.75 229.92 161.83 12.93 25.15 19.04

ΔLogCFU/thigh

± ± ± ± ±

0.20 3.51 4.07 4.40 4.49

7.86 4.55 3.99 3.66 3.57

0.77 1.45 1.55 0.49 1.59

PRECLINICAL SAFETY PROFILE FOR COMPOUND 7 Compound 7 was evaluated with a close attention to the oxazolidinone-class toxicity effects. In vitro bone marrow myelosuppression CD34+ data were noted above (Table 3) in the context of the lead selection and the apparent differentiation of compound 7 from both linezolid and the newer clinical candidate tedizolid.20b To ascertain myelosuppressive potential of compound 7 in vivo, a 4-week repeated dose study in rat was performed (as originally reported by Qiu23f). The study was designed to maximize the potential toxicity within a broad range of the drug exposure. Compound 7 was administered orally twice daily (10 rats/gender/group) at doses of 20, 100, and 200/300 mg/kg/ day for 4 weeks, followed by a 4-week recovery period. Because of a lack of apparent toxicity, the top dose of 200 mg/kg/day was escalated to 300 mg/kg/day on day 15. The linezolid comparator was dosed in a similar manner at 100 and 200 mg/ kg/day. Blood samples were collected for toxicokinetic (TK) analysis on days 1, 14, and 28. Notably, no mortality was observed in any of compound 7 groups. In contrast, all female rats in the linezolid 200 mg/kg/ day group were deceased by day 14, with apparent signs of myelosuppression, including cachexia and pronounced body weight loss. In the linezolid 100 mg/kg/day cohort, female rats exhibited notably reduced weight gain during the first 2 weeks

Table 11. PK Parameters of the Compound 7 in Rat dose (mg/kg) (route)

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LogCFU/thigh

1.5, and 3 h; and the oral bioavailability was 69%, 109%, and 37%. Similar to linezolid, a gender bias was observed in rat, with somewhat higher exposure in females vs males. No gender difference was observed in mouse or dog. No significant drug accumulation was observed during 7-days repeated dose studies in either rat or dog. G



Drug Annotation

Table 12. Compound 7 Repeated Dose Toxicity: Hematology Parameters in Female Rata compound 7

linezolid

parameter

0

20 (mg/kg/day)

100 (mg/kg/day)

200−300 (mg/kg/day)

100 (mg/kg/day)

WBC (109/L) RBC (1012/L) HB (g/L) HCT (%) MCV (fL) MCH (pg) PLT (109/L) N (%) L (%) RET (%)

3.66 7.28 141.8 39.08 53.72 19.5 654.6 22.4 74.8 1.48

4.5 6.82 137.8 37.16 54.52 20.2 638.2 15.4 83.4 1.3

3.14 6.67 134.8 36.48 54.78 20.28 636.2 18.4 78.8 1.46

2.72 5.77 117.6 30.6 53.02 20.48 464.2 26.4 71.8 1.26

1.9 5.52 112.8 30.18 54.74 20.52 487.4 13 86.2 1.64

a

WBC, white blood cells; RBC, red blood cells; HB, hemoglobin; HCT, hematocrit;. MCV, mean corpuscular volume; MCH, mean corpuscular hemoglobin; PLT, platelets; N, neutrophils; L, lymphocytes; RET, reticulocytes.

reported by Wang;23e Table 13). These results are in general agreement with the data from independently performed bioluminescent assay.33

and stopped gaining weight thereafter. In contrast, female rats dosed with 20 and 100 mg/kg/day of compound 7 maintained normal rate of weight gain throughout 4 weeks of the test period. Furthermore, a hematologic analysis has revealed a pronounced drop in the white blood cell (WBC) count in 100 mg/kg/day female and in 200 mg/kg/day male rat cohorts for linezolid (Table 12). In contrast, this decline was attenuated for compound 7 in the 200−300 mg/kg/day female rat group, and no WBC decline was observed in any of the other compound 7 test groups. Reductions in platelet counts were observed at 100 mg/kg/day linezolid, but not at 100 mg/kg/ day for compound 7, indicating a lower thrombocytopenia potential for the new agent (Table 12). The data indicate a significantly attenuated hematological toxicity for compound 7 as compared to linezolid, including the propensity to cause thrombocytopenia noted as a warning in the prescribing information for linezolid.14 The histopathology revealed apparent changes in the bone marrow for linezolid in 100 mg/kg/day female and 200 mg/kg/ day male rat groups. Some bone marrow changes were noted for compound 7 in the 200−300 mg/kg/day female rat group only, with no abnormality observed after the recovery period. TK analysis confirmed the high exposure to compound 7 throughout the 4-week repeated dose study, with Cmax and AUC0−t increasing in a dose-proportional manner. No drug accumulation was noted after 28 days of the repeat dosing. Consistent with the gender drug effect, the exposure to compound 7 was somewhat higher in female rats compared to male rats. Female rat AUC0−24 values were within the range of 319−357 μg·h/mL for 100 mg/kg/day dosing and 626−650 μg·h/mL for 200 mg/kg/day dosing. Importantly, compound 7 exposure at 100 mg/kg/day was similar to that reported for linezolid at 125 mg/kg/day, with AUC value of 373 μg·h/mL reported36 for the comparator drug. The repeat-dose no observed adverse effects level (NOAEL) for compound 7 was determined as 100 mg/kg/day. Single-dose acute toxicity in rat for this agent was determined as 5000 mg/kg. Thus, consistent with the attenuated cytotoxicity of the new agent in the human bone marrow CD34+ assay, the preclinical animal data also suggest a notably reduced myelosuppressive potential for compound 7 as compared to linezolid, with similar exposure for the two agents. As noted already, MAOI is independent of the myelosuppression toxicity. The attenuated MAOI for compound 7 was additionally confirmed in a fluorescent assay36 (as originally

Table 13. MAO-A Inhibition of Compound 7 and Comparator Linezolid MAO-A IC50 (μg/mL) (mean ± SD) assay system bioluminscent fluorescentb a

a

compound 7

linezolid

12.3 ± 1.1 41.9 ± 1.3

4.1 ± 1.0 8.1 ± 1.2

MAO assay of ref 33. bMAO assay of ref 37.

Thus, MAOI for the new agent is 3−5-fold reduced over the comparator linezolid, as confirmed in two in vitro MAO-A assays. The data indicate a significantly improved safety potential for the compound 7 with respect to its potential for adverse effects and/or drug−drug interactions due to the MAOI listed in the prescribing information for linezolid.14 Preclinical toxicity evaluation also included CYP450 enzymes inhibition assay (at 0−200 μM of compound 7), chromosomal aberration testing with Chinese hamster lung (CHL) cells (at 50−400 μg/mL of compound 7 over 6 h and at 25−200 μg/ mL of compound 7 over 24 h), and mutagenic potential assessment in L5178Y tk± mouse lymphoma cell assay (with and without S9 factor, at 62.5−1000 μg/mL of compound 7).23e The new agent did not exhibit significant inhibition of CYP3A4, CYP1A2, CYP2C9, CYP2C19, and CYP2D6. For CYP2E1, a modest inhibition was detected, with IC50 value of 9.6 μM. In the chromosomal aberration study, compound 7 did not induce structural chromosome aberration in CHL cells with or without metabolic activation. No increase in the gene mutation frequency was observed. Thus, compound 7 did not exhibit any apparent toxicity in CYP inhibition, clastogenicity, and mutagenicity assays.

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EARLY CLINICAL SAFETY AND TOLERABILITY OF COMPOUND 7 IN PHASE I TRIAL The distinct safety potential of the new oxazolidinone established in preclinical studies warranted its advance into the clinical evaluation. Phase I clinical trial of compound 7 was designed as a single-dose study followed by multiple dose evaluations, with attention to drug exposure, food effects, safety, and tolerability. H



Drug Annotation

mL under fasting condition to 141.1 μg·h/mL for fed subjects and with a concomitant Cmax increase from 18.1 to 42.3 μg/mL (Table 15). Thus, the oral absorption and elimination half-life of compound 7 increased with escalating single dosing in the range of 300−900 mg. Meal consumption significantly increased the oral absorption without affecting the time required to achieve the peak concentration of the drug. Next, a randomized, double-blind, placebo-controlled multiple-dose safety and PK study was conducted in 32 healthy subjects, half male and half female (as originally reported by Zhang23h). Each cohort of four subjects (two of each gender) received placebo, and 12 received 28 doses of 600 or 800 mg of compound 7 over 15 days, with each dose taken with a meal. Single dose of the agent was administered on days 1 and 15 for full PK determination, followed by two doses administered Q12h (BID) from day 2 to day 14. Clinical observations including vital signs and physical examination, and laboratory tests including hematology and blood chemistry were performed throughout the study course. Compound 7 was well tolerated in healthy subjects at 600 mg and 800 mg BID dosing for 15 days with no serious adverse events. PK parameters are illustrated in Table 16 below. As clear from the data, the new agent exhibited high exposure levels at 600 and 800 mg BID dosing for 15 days, with values similar to those reported for linezolid. The mean Cmax and AUC values increased proportionally with escalating dose, reaching a steady state on day 3. No drug accumulation was observed. Exposure levels of compound 7 on day 1 and day 15 were similar. The mean AUC values on days 1 and 15 were 68.61 and 72.91 μg·h/mL (respectively) for 600 mg group, and 91.85 vs 90.38 μg·h/mL (respectively) for the 800 mg cohort. Importantly, the key hematology parameters remained unchanged during the entire course of the study, suggesting a low propensity of compound 7 to induce myelosuppresion. No significant changes in hematologic parameters, including platelet, reticulocyte, neutrophil, and red blood cell counts, were detected over the course of the study, as illustrated by the representative data of Figure 3. Thus, compound 7 was well tolerated in a human phase I clinical trial, with key hematology markers indicating a notably attenuated myelosuppression potential compared to that reported for linezolid9,38 and consistent with preclinical data for the agent, including reduced human bone marrow toxicity and MAOI.

Table 14. Single-Dose Human PK for the Compound 7 in Fasting Subjects, Noncompartmental Model parameter

300 mg dose

600 mg dose

900 mg dose

Cmax (μg/mL) Tmax (h) AUC0−inf (μg·h/mL) T1/2 (h)

8.07 1.25 29.22 2.18

12.24 2 48.26 3.31

15.25 1.5 59.16 4.94

Table 15. Single-Dose Human PK for Compound 7: Food Effect at 900 mg/kg Dosing parameter

without food

with food

Cmax (μg/mL) Tmax (h) AUC0‑inf (μg·h/mL) T1/2 (h)

18.1 1.4 66.57 4.9

42.3 1.63 141.14 2.7

Table 16. Compound 7 PK in Multiple Ascending Oral Dose Study: Day 1 and Day 15 600 mg

800 mg

parameter/day

day 1

day 15

day 1

day 15

Cmax (μg/mL) Tmax (h) AUC0−24 (μg·h/mL)

20.34 0.65 68.61

20.61 0.6 72.91

27.8 0.85 91.85

26.45 0.57 90.38

The single ascending dose tolerability study was a randomized, double-blind, placebo-controlled study in healthy Chinese subjects (as originally reported by Zhang23g). Eight treatment groups were administered oral compound 7 at doses ranging from 50 to 1800 mg under fasting conditions (50, 100, 200, 400, 800, 1200, 1600, and 1800 mg). The new agent was well tolerated in all dosing groups. In a single-dose, three-period, Latin-square crossover study, 12 healthy volunteers (six of each gender) received (under fasting conditions) single oral doses of 300, 600, and 900 mg of compound 7, with a 1-week washout between doses. In a separate crossover study, 12 subjects (six of each gender) received a single oral dose of 900 mg of the agent either under fasting condition or 30 min after a meal. Compound 7 was quickly absorbed, achieving a peak concentration within 1−2 h of the oral administration. In fasting subjects, mean Tmax values ranged from 1.3 to 2.0 h, and mean T1/2 ranged from 2.2 to 4.9 h (Table 14). The mean Cmax and AUC0−inf values increased with escalated dosing, ranging from 8.1 to 15.3 μg/mL and 29.2 to 59.2 μg·h/mL, respectively. Consumption of a fat-containing meal facilitated compound 7 absorption, with AUC0−inf values increased from 66.6 μg·h/

Figure 3. Hematology for compound 7 in the human multiple oral dose study: platelet and reticulocyte markers of the myelosuppression toxicity. I



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Drug Annotation

CONCLUSION Clinical compound 7 is a novel oxazolidinone with a broad Gram-positive antibacterial spectrum and an improved over linezolid potency against widespread pathogen MRSA. Notably, the high activity and oral bioavailability of the new agent are coupled with markedly attenuated myelosuppression and MAOI. This long sought-after feature in a new oxazolidinone offers a potential to minimize the limiting adverse effects encountered in linezolid therapy, primarily associated with the bone marrow toxicity and serotonergic drug−drug interactions. Initial clinical data for compound 7 warrant its further evaluation as a next-generation oxazolidinone that may supplant current linezolid therapy. The new agent may fulfill the need for a safer oxazolidinone for the long-term treatment of persistent Gram-positive infections. This clinical agent may prove particularly useful in patient populations where myelosuppression and MAOI must be avoided, including patients predisposed to myelosuppression, such as HIV patients, and subjects receiving a concomitant therapy with bone marrow suppressive drugs, such as cancer patients.

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penicillin-sensitive Streptococcus pneumoniae; VSE, vancomycin-sensitive Enterococci; HLGR, high-level gentamycinresistant; VAN-S, vancomycin-sensitive; PAE, postantibiotic effect; AUC, area under the curve; CFU, colony-forming units; PK, pharmacokinetics; WBC, white blood cells; RBC, red blood cells; HB, hemoglobin; HCT, hematocrit; MCV, mean corpuscular volume; MCH, mean corpuscular hemoglobin; PLT, platelets; N, neutrophils; L, lymphocytes; RET, reticulocytes; NOAEL, no observed adverse effects level; BID, twice daily; Q12h, administration with 12 h interval between doses

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REFERENCES

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AUTHOR INFORMATION

Corresponding Author

*Phone: 510 782-2022. E-mail: [email protected]. Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS The work reviewed herein was performed by several teams of MicuRx scientists and collaborators both in the USA and P.R. China. Critical contributions were made by our MicuRx colleagues Wen Wang, Jinqian (Jim) Liu, Yanqing (Amy) Huang, Hong Yuan, Feng Zhou, Chun Liu, Changqing Wang, Shicong Liu, Yunhua Xu, Hailing Wang, Huiping Liu, Tony Fu, Qiang Wang, and our collaborators at the HuaShan Hospital of Fudan University (led by Yingyuan Zhang, Jing Zhang, and Demei Zhu), the Institute of Medicinal Biotechnology at Chinese Academy of Medical Sciences (Xuefu Liu), the Shanghai Institute of Materia Medica at Chinese Academy of Sciences (led by Dafang Zhong and Xiaoyan Chen), and the National Shanghai Center for Drug Safety Evaluation & Research (led by Jin Ma). We express deep gratitude for their scientific insight and the diligent efforts that made this progress possible. Edits by A. M. Gordeev and P. S. Margolis are also acknowledged.

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ABBREVIATIONS USED MAOI, monoamine oxidase inhibition; COX-2, cyclooxygenase-2; FDA, the Food and Drug Administration; MDR, multidrug-resistant; SAR, structure−activity relationship; MIC90, minimum concentration to inhibit the growth of 90% strains tested; MRSA, methicillin-resistant Staphylococcus aureus; MIC, minimum inhibitory concentration; MIC90, minimum inhibitory concentration to inhibit the growth of 90% strains tested; VRE, vancomycin-resistant enterococci; MAO, monoamine oxidase; MAO-A, monoamine oxidase subtype A; ED50, effective dose for 50% survival; CD34+, human bone marrow cells; ATCC, American Type Culture Collection; MSSA, methicillin-sensitive Staphylococcus aureus; MRSE, methicillin-resistant Staphylococcus epidermidis; PISP, penicillin intermediate-sensitive Streptococcus pneumoniae; PRSP, penicillin-resistant Streptococcus pneumoniae; PSSP, J



Drug Annotation

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New Potent Antibacterial Oxazolidinone (MRX-I) with an Improved

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