title: Substituted Indazoles as Nav1.7 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.
authors.affiliation: Research and Development, AbbVie , 1 North Waukegan Road, North Chicago, Illinois 60064, United States.
authors.forename: Jennifer M
authors.initials: JM
authors.lastname: Frost
authors.affiliation: Research and Development, AbbVie , 1 North Waukegan Road, North Chicago, Illinois 60064, United States.
authors.forename: David A
authors.initials: DA
authors.lastname: DeGoey
authors.affiliation: Research and Development, AbbVie , 1 North Waukegan Road, North Chicago, Illinois 60064, United States.
authors.forename: Lei
authors.initials: L
authors.lastname: Shi
authors.affiliation: Research and Development, AbbVie , 1 North Waukegan Road, North Chicago, Illinois 60064, United States.
authors.forename: Rebecca J
authors.initials: RJ
authors.lastname: Gum
authors.affiliation: Research and Development, AbbVie , 1 North Waukegan Road, North Chicago, Illinois 60064, United States.
authors.forename: Meagan M
authors.initials: MM
authors.lastname: Fricano
authors.affiliation: Research and Development, AbbVie , 1 North Waukegan Road, North Chicago, Illinois 60064, United States.
authors.forename: Greta L
authors.initials: GL
authors.lastname: Lundgaard
authors.affiliation: Research and Development, AbbVie , 1 North Waukegan Road, North Chicago, Illinois 60064, United States.
authors.forename: Odile F
authors.initials: OF
authors.lastname: El-Kouhen
authors.affiliation: Research and Development, AbbVie , 1 North Waukegan Road, North Chicago, Illinois 60064, United States.
authors.forename: Gin C
authors.initials: GC
authors.lastname: Hsieh
authors.affiliation: Research and Development, AbbVie , 1 North Waukegan Road, North Chicago, Illinois 60064, United States.
authors.forename: Torben
authors.initials: T
authors.lastname: Neelands
authors.affiliation: Research and Development, AbbVie , 1 North Waukegan Road, North Chicago, Illinois 60064, United States.
authors.forename: Mark A
authors.initials: MA
authors.lastname: Matulenko
authors.affiliation: Research and Development, AbbVie , 1 North Waukegan Road, North Chicago, Illinois 60064, United States.
authors.forename: Jerome F
authors.initials: JF
authors.lastname: Daanen
authors.affiliation: Research and Development, AbbVie , 1 North Waukegan Road, North Chicago, Illinois 60064, United States.
authors.forename: Madhavi
authors.initials: M
authors.lastname: Pai
authors.affiliation: Aptinyx , 1801 Maple Avenue, No. 4300, Evanston, Illinois 60201, United States.
authors.forename: Nayereh
authors.initials: N
authors.lastname: Ghoreishi-Haack
authors.affiliation: Research and Development, AbbVie , 1 North Waukegan Road, North Chicago, Illinois 60064, United States.
authors.forename: Cenchen
authors.initials: C
authors.lastname: Zhan
authors.affiliation: Research and Development, AbbVie , 1 North Waukegan Road, North Chicago, Illinois 60064, United States.
authors.forename: Xu-Feng
authors.initials: XF
authors.lastname: Zhang
authors.affiliation: Research and Development, AbbVie , 1 North Waukegan Road, North Chicago, Illinois 60064, United States.
authors.forename: Michael E
authors.initials: ME
authors.lastname: Kort
mesh_terms: D000700:Analgesics / Q000737:chemistry / Q000494:pharmacology*; D000818:Animals; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004594:Electrophysiology; D005071:Evoked Potentials; D048289:Imidazolidines / Q000737:chemistry / Q000494:pharmacology*; D007191:Indazoles / Q000737:chemistry / Q000494:pharmacology*; D019807:Iodoacetic Acid / Q000633:toxicity; D015394:Molecular Structure; D062556:NAV1.7 Voltage-Gated Sodium Channel / Q000737:chemistry* / Q000378:metabolism; D010003:Osteoarthritis / Q000139:chemically induced / Q000188:drug therapy* / Q000378:metabolism; D010146:Pain / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D010147:Pain Measurement; D011758:Pyrroles / Q000737:chemistry / Q000494:pharmacology*; D051381:Rats; D026941:Sodium Channel Blockers / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: C000611068:1-(1-(2-fluorophenyl)-1H-indazol-4-yl)-3-(2-(3-fluoropyrrolidin-1-yl)-2-oxoethyl)imidazolidin-2-one; C000611069:2-(1-(2-fluorophenyl)-1H-indazol-4-yl)-5-(3-hydroxy-3-methylbutanoyl)hexahydropyrrolo(3,4-c)pyrrol-1(2H)-one; D000700:Analgesics; D048289:Imidazolidines; D007191:Indazoles; D062556:NAV1.7 Voltage-Gated Sodium Channel; D011758:Pyrroles; D026941:Sodium Channel Blockers; D019807:Iodoacetic Acid