Substituted Indazoles as Na_v1.7 Blockers for the Treatment of Pain

The genetic validation for the role of the Na_v1.7 voltage-gated ion channel in pain signaling pathways makes it an appealing target for the potential development of new pain drugs. The utility of nonselective Na_v blockers is often limited due to adverse cardiovascular and CNS side effects. We sought more selective Na_v1.7 blockers with oral activity, improved selectivity, and good druglike properties. The work described herein focused on a series of 3- and 4-substituted indazoles. SAR studies of 3-substituted indazoles yielded analog <b>7</b> which demonstrated good in vitro and in vivo activity but poor rat pharmacokinetics. Optimization of 4-substituted indazoles yielded two compounds, <b>27</b> and <b>48</b>, that exhibited good in vitro and in vivo activity with improved rat pharmacokinetic profiles. Both <b>27</b> and <b>48</b> demonstrated robust activity in the acute rat monoiodoacetate-induced osteoarthritis model of pain, and subchronic dosing of <b>48</b> showed a shift to a lower EC₅₀ over 7 days

Substituted Indazoles as Na_v1.7 Blockers for the Treatment of Pain

The genetic validation for the role of the Na_v1.7 voltage-gated ion channel in pain signaling pathways makes it an appealing target for the potential development of new pain drugs. The utility of nonselective Na_v blockers is often limited due to adverse cardiovascular and CNS side effects. We sought more selective Na_v1.7 blockers with oral activity, improved selectivity, and good druglike properties. The work described herein focused on a series of 3- and 4-substituted indazoles. SAR studies of 3-substituted indazoles yielded analog <b>7</b> which demonstrated good in vitro and in vivo activity but poor rat pharmacokinetics. Optimization of 4-substituted indazoles yielded two compounds, <b>27</b> and <b>48</b>, that exhibited good in vitro and in vivo activity with improved rat pharmacokinetic profiles. Both <b>27</b> and <b>48</b> demonstrated robust activity in the acute rat monoiodoacetate-induced osteoarthritis model of pain, and subchronic dosing of <b>48</b> showed a shift to a lower EC₅₀ over 7 days

Discovery of ABT-267, a Pan-Genotypic Inhibitor of HCV NS5A

We describe here <i>N</i>-phenylpyrrolidine-based inhibitors of HCV NS5A with excellent potency, metabolic stability, and pharmacokinetics. Compounds with 2<i>S</i>,5<i>S</i> stereochemistry at the pyrrolidine ring provided improved genotype 1 (GT1) potency compared to the 2<i>R</i>,5<i>R</i> analogues. Furthermore, the attachment of substituents at the 4-position of the central <i>N</i>-phenyl group resulted in compounds with improved potency. Substitution with <i>tert</i>-butyl, as in compound <b>38</b> (ABT-267), provided compounds with low-picomolar EC₅₀ values and superior pharmacokinetics. It was discovered that compound <b>38</b> was a pan-genotypic HCV inhibitor, with an EC₅₀ range of 1.7–19.3 pM against GT1a, -1b, -2a, -2b, -3a, -4a, and -5a and 366 pM against GT6a. Compound <b>38</b> decreased HCV RNA up to 3.10 log₁₀ IU/mL during 3-day monotherapy in treatment-naive HCV GT1-infected subjects and is currently in phase 3 clinical trials in combination with an NS3 protease inhibitor with ritonavir (r) (ABT-450/r) and an NS5B non-nucleoside polymerase inhibitor (ABT-333), with and without ribavirin

Highlights of the Structure–Activity Relationships of Benzimidazole Linked Pyrrolidines Leading to the Discovery of the Hepatitis C Virus NS5A Inhibitor Pibrentasvir (ABT-530)

Curative interferon and ribavirin sparing treatments for hepatitis C virus (HCV)-infected patients require a combination of mechanistically orthogonal direct acting antivirals. A shared component of these treatments is usually an HCV NS5A inhibitor. First generation FDA approved treatments, including the component NS5A inhibitors, do not exhibit equivalent efficacy against HCV virus genotypes 1–6. In particular, these first generation NS5A inhibitors tend to select for viral drug resistance. Ombitasvir is a first generation HCV NS5A inhibitor included as a key component of Viekira Pak for the treatment of patients with HCV genotype 1 infection. Since the launch of next generation HCV treatments, functional cure for genotype 1–6 HCV infections has been achieved, as well as shortened treatment duration across a wider spectrum of genotypes. In this paper, we show how we have modified the anchor, linker, and end-cap architecture of our NS5A inhibitor design template to discover a next generation NS5A inhibitor pibrentasvir (ABT-530), which exhibits potent inhibition of the replication of wild-type genotype 1–6 HCV replicons, as well as improved activity against replicon variants demonstrating resistance against first generation NS5A inhibitors