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

Abstract

The genetic validation for the role of the Nav1.7 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 Nav blockers is often limited due to adverse cardiovascular and CNS side effects. We sought more selective Nav1.7 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 7 which demonstrated good in vitro and in vivo activity but poor rat pharmacokinetics. Optimization of 4-substituted indazoles yielded two compounds, 27 and 48, that exhibited good in vitro and in vivo activity with improved rat pharmacokinetic profiles. Both 27 and 48 demonstrated robust activity in the acute rat monoiodoacetate-induced osteoarthritis model of pain, and subchronic dosing of 48 showed a shift to a lower EC50 over 7 days.

Selective NaV1.7 Antagonists with Long Residence Time Show Improved Efficacy against Inflammatory and Neuropathic Pain

“…Amitriptyline is a potent sodium channel blocker that suppresses neuropathic pain after chronic dosing, but not after a single dose (Benbouzid et al, 2008). Likewise, our results are consistent with a repeat dose study with an indazole Na V antagonist tested in an osteoarthritic pain model (Frost et al, 2016) and with a TRPV1 antagonist (Honore et al, 2009). Third, nerve block with a local anesthetic results in long-lasting inhibition of mechanical allodynia due to nerve injury (Xie et al, 2005), very reminiscent of the very slow reversal of analgesia seen in our studies (Figure 6E).…”

Pharmacologic Characterization of AMG8379, a Potent and Selective Small Molecule Sulfonamide Antagonist of the Voltage-Gated Sodium Channel NaV1.7

“…Our findings are consistent with reports that poorly selective or Na V 1.7-prefering small-molecule antagonists can block spontaneous or evoked pain responses in preclinical species (Brochu et al, 2006;Haroutounian et al, 2014;Matson et al, 2015;Alexandrou et al, 2016;Deuis et al, 2016;Focken et al, 2016;Frost et al, 2016;Hockley et al, 2017). Clinically, a small cohort of individuals with Na V 1.7 gain-of-function mutations causing inherited erythromelalgia exhibited lower pain scores in response to thermal challenge after short-term dosing with a sulfonamide antagonist (Cao et al, 2016).…”

Synthetic Exploration of α‐Diazo γ‐Butyrolactams

“…Alternatively, this transformation may proceed via protonation of the α‐diazocarbonyl moiety followed by elimination of a nitrogen molecule. 3‐Pyrrolin‐2‐ones are versatile substrates for addition of organometallic compounds, Michael addition and 1,3‐dipolar cycloaddition . At the same time, the principal methods employed in their preparation are olefin metathesis and oxidative elimination of α‐phenylselenyl lactams , .…”