Discovery of DS-1971a, a Potent, Selective Na_V1.7 Inhibitor

Abstract

A highly potent, selective NaV1.7 inhibitor, DS-1971a, has been discovered. Exploration of the left-hand phenyl ring of sulfonamide derivatives (I and II) led to the discovery of novel series of cycloalkane derivatives with high NaV1.7 inhibitory potency in vitro. As the right-hand heteroaromatic ring affected the mechanism-based inhibition liability of CYP3A4, replacement of this moiety resulted in the generation of 4-pyrimidyl derivatives. Additionally, GSH adducts formation, which can cause idiosyncratic drug toxicity, was successfully avoided by this modification. An additional optimization led to the discovery of DS-1971a. In preclinical studies, DS-1971a demonstrated highly potent selective in vitro profile with robust efficacy in vivo. DS-1971a exhibited a favorable toxicological profile, which enabled multiple-dose studies of up to 600 mg bid or 400 mg tid (1200 mg/day) administered for 14 days to healthy human males. DS-1971a is expected to exert potent efficacy in patients with peripheral neuropathic pain, with a favorable safety profile.

CYP2C8-Mediated Formation of a Human Disproportionate Metabolite of the Selective NaV1.7 Inhibitor DS-1971a, a Mixed Cytochrome P450 and Aldehyde Oxidase Substrate

“…Plasma protein binding of M1 in humans was 98%. High plasma protein binding of M1 was in agreement with that of DS-1971a (99%) (Shinozuka et al, 2020). These values were used to assess drug-drug interaction potential and contribution to efficacy by calculating the free plasma concentration of DS-1971a and M1 in humans.…”

“…M1 has less pharmacological activity than DS-1971a: IC 50 values for Na v 1.7 of M1 and DS-1971a were 0.31 (data not shown) and 0.02 μM (Shinozuka et al, 2020), indicating the minimal contribution of M1 to human efficacy because its maximum free plasma concentration at 400 mg (0.13 μM) was below IC 50 value. M1 exposure in monkeys (5710 ng•h/mL) at a dose of 1000 mg/kg was relatively close to that in humans (18400 ng•h/mL), but we have not explored doses over 1000 mg/kg because a limit dose is set as 1000 mg/kg when saturated exposure (Supplementary Table S2) is observed in the ICH M3(R2) guidance (ICH, 2010).…”

“…Protein Binding of M1 in Human Plasma. Manuscript number: DMD-AR-2021-000665 14 Protein binding rate of M1 in human plasma was determined in vitro as described previously (Shinozuka et al, 2020).…”

“…DS-1971a (Fig. 1) is a selective inhibitor of the Na v 1.7 voltage-gated sodium channel that is under development for the treatment of neuropathic pain (Shinozuka et al, 2020). The oral bioavailability of DS-1971a was moderate to high in monkeys (35%) and dogs (77%), and potent pain relief was observed in a neuropathic pain mouse model after oral administration.…”

“…Mice and monkeys were selected as general toxicity animals from a viewpoint of pharmacological activity and AO metabolism. Non-clinical safety studies Manuscript number: DMD-AR-2021-000665 6 revealed a wide safety margin, with a no observed adverse effect level of 1000 mg/kg, the highest dose tested in 6-or 9-month repeated-dose toxicity studies in mice and monkeys (Shinozuka et al, 2020). In a Phase 1 single ascending dose study in healthy human subjects, DS-1971a was tolerable up to a dose of 1500 mg (https://clinicaltrials.gov/ct2/show/record/NCT02107885), and its effective human dose was estimated to be 400 mg based on exposure levels in a Phase 1 multiple ascending dose study (https://clinicaltrials.gov/ct2/show/NCT02190058).…”