title: Aminopiperidine sulfonamide Cav2.2 channel inhibitors for the treatment of chronic pain.
abstract: The voltage-gated calcium channel Ca(v)2.2 (N-type calcium channel) is a critical regulator of synaptic transmission and has emerged as an attractive target for the treatment of chronic pain. We report here the discovery of sulfonamide-derived, state-dependent inhibitors of Ca(v)2.2. In particular, 19 is an inhibitor of Ca(v)2.2 that is selective over cardiac ion channels, with a good preclinical PK and biodistribution profile. This compound exhibits dose-dependent efficacy in preclinical models of inflammatory hyperalgesia and neuropathic allodynia and is devoid of ancillary cardiovascular or CNS pharmacology at the doses tested. Importantly, 19 exhibited no efficacy in Ca(v)2.2 gene-deleted mice. The discovery of metabolite 26 confounds further development of members of this aminopiperidine sulfonamide series. This discovery also suggests specific structural liabilities of this class of compounds that must be addressed.
authors.affiliation: Departments of Medicinal Chemistry, Merck Research Laboratories, Rahway, New Jersey 07065, USA. pengcheng.shao@merck.com
authors.forename: Pengcheng P
authors.initials: PP
authors.lastname: Shao
authors.forename: Feng
authors.initials: F
authors.lastname: Ye
authors.forename: Prasun K
authors.initials: PK
authors.lastname: Chakravarty
authors.forename: Deepu J
authors.initials: DJ
authors.lastname: Varughese
authors.forename: James B
authors.initials: JB
authors.lastname: Herrington
authors.forename: Ge
authors.initials: G
authors.lastname: Dai
authors.forename: Randal M
authors.initials: RM
authors.lastname: Bugianesi
authors.forename: Rodolfo J
authors.initials: RJ
authors.lastname: Haedo
authors.forename: Andrew M
authors.initials: AM
authors.lastname: Swensen
authors.forename: Vivien A
authors.initials: VA
authors.lastname: Warren
authors.forename: McHardy M
authors.initials: MM
authors.lastname: Smith
authors.forename: Maria L
authors.initials: ML
authors.lastname: Garcia
authors.forename: Owen B
authors.initials: OB
authors.lastname: McManus
authors.forename: Kathryn A
authors.initials: KA
authors.lastname: Lyons
authors.forename: Xiaohua
authors.initials: X
authors.lastname: Li
authors.forename: Mitchell
authors.initials: M
authors.lastname: Green
authors.forename: Nina
authors.initials: N
authors.lastname: Jochnowitz
authors.forename: Erin
authors.initials: E
authors.lastname: McGowan
authors.forename: Shruti
authors.initials: S
authors.lastname: Mistry
authors.forename: Shu-Yu
authors.initials: SY
authors.lastname: Sun
authors.forename: Catherine
authors.initials: C
authors.lastname: Abbadie
authors.forename: Gregory J
authors.initials: GJ
authors.lastname: Kaczorowski
authors.forename: Joseph L
authors.initials: JL
authors.lastname: Duffy
mesh_terms: D000818:Animals; D002121:Calcium Channel Blockers / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000494:pharmacology*; D020864:Calcium Channels, N-Type / Q000737:chemistry* / Q000378:metabolism / Q000502:physiology*; D002478:Cells, Cultured; D059350:Chronic Pain / Q000188:drug therapy*; D004285:Dogs; D006801:Humans; D006930:Hyperalgesia / Q000188:drug therapy*; D007249:Inflammation / Q000188:drug therapy*; D051379:Mice; D018345:Mice, Knockout; D008862:Microsomes, Liver / Q000187:drug effects; D009437:Neuralgia / Q000188:drug therapy*; D018408:Patch-Clamp Techniques; D010880:Piperidines / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013449:Sulfonamides / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000494:pharmacology*; D014018:Tissue Distribution; D000096926:Benzenesulfonamides
chemical_list: D002121:Calcium Channel Blockers; D020864:Calcium Channels, N-Type; D010880:Piperidines; D013449:Sulfonamides; C500963:Cacna1b protein, mouse; C503279:Cacna1b protein, rat; C577943:N-cyclopropyl-N-(1-((5-fluoro-2-(methylsulfonyl)phenyl)carbonyl)piperidin-4-yl)-3-(trifluoromethyl)benzenesulfonamide; D000096926:Benzenesulfonamides