Substituted Indazoles as Nav1.7 Blockers for the Treatment of Pain

Jennifer M Frost; David A DeGoey; Lei Shi; Rebecca J Gum; Meagan M Fricano; Greta L Lundgaard; Odile F El-Kouhen; Gin C Hsieh; Torben Neelands; Mark A Matulenko; Jerome F Daanen; Madhavi Pai; Nayereh Ghoreishi-Haack; Cenchen Zhan; Xu-Feng Zhang; Michael E Kort

doi:10.1021/acs.jmedchem.6b00063

Substituted Indazoles as Nav1.7 Blockers for the Treatment of Pain

J Med Chem. 2016 Apr 14;59(7):3373-91. doi: 10.1021/acs.jmedchem.6b00063. Epub 2016 Apr 5.

Authors

Jennifer M Frost¹, David A DeGoey¹, Lei Shi¹, Rebecca J Gum¹, Meagan M Fricano¹, Greta L Lundgaard¹, Odile F El-Kouhen¹, Gin C Hsieh¹, Torben Neelands¹, Mark A Matulenko¹, Jerome F Daanen¹, Madhavi Pai¹, Nayereh Ghoreishi-Haack², Cenchen Zhan¹, Xu-Feng Zhang¹, Michael E Kort¹

Affiliations

¹ Research and Development, AbbVie , 1 North Waukegan Road, North Chicago, Illinois 60064, United States.
² Aptinyx , 1801 Maple Avenue, No. 4300, Evanston, Illinois 60201, United States.

PMID: 27015369
DOI: 10.1021/acs.jmedchem.6b00063

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.

MeSH terms

Analgesics / chemistry
Analgesics / pharmacology*
Animals
Disease Models, Animal
Dose-Response Relationship, Drug
Electrophysiology
Evoked Potentials
Imidazolidines / chemistry
Imidazolidines / pharmacology*
Indazoles / chemistry
Indazoles / pharmacology*
Iodoacetic Acid / toxicity
Molecular Structure
NAV1.7 Voltage-Gated Sodium Channel / chemistry*
NAV1.7 Voltage-Gated Sodium Channel / metabolism
Osteoarthritis / chemically induced
Osteoarthritis / drug therapy*
Osteoarthritis / metabolism
Pain / drug therapy*
Pain / metabolism
Pain / pathology
Pain Measurement
Pyrroles / chemistry
Pyrroles / pharmacology*
Rats
Sodium Channel Blockers / chemistry
Sodium Channel Blockers / pharmacology*
Structure-Activity Relationship

Substances

1-(1-(2-fluorophenyl)-1H-indazol-4-yl)-3-(2-(3-fluoropyrrolidin-1-yl)-2-oxoethyl)imidazolidin-2-one
2-(1-(2-fluorophenyl)-1H-indazol-4-yl)-5-(3-hydroxy-3-methylbutanoyl)hexahydropyrrolo(3,4-c)pyrrol-1(2H)-one
Analgesics
Imidazolidines
Indazoles
NAV1.7 Voltage-Gated Sodium Channel
Pyrroles
Sodium Channel Blockers
Iodoacetic Acid