title: A novel series of pyrazolylpiperidine N-type calcium channel blockers.
abstract: Selective blockers of the N-type calcium channel have proven to be effective in animal models of chronic pain. However, even though intrathecally delivered synthetic ω-conotoxin MVIIA from Conus magnus (ziconotide [Prialt®]) has been approved for the treatment of chronic pain in humans, its mode of delivery and narrow therapeutic window have limited its usefulness. Therefore, the identification of orally active, small-molecule N-type calcium channel blockers would represent a significant advancement in the treatment of chronic pain. A novel series of pyrazole-based N-type calcium channel blockers was identified by structural modification of a high-throughput screening hit and further optimized to improve potency and metabolic stability. In vivo efficacy in rat models of inflammatory and neuropathic pain was demonstrated by a representative compound from this series.
authors.affiliation: Janssen Research & Development, L.L.C., Welsh & McKean Roads, Spring House, PA 19477, USA. NSUBASIN@its.jnj.com
authors.forename: Nalin L
authors.initials: NL
authors.lastname: Subasinghe
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Wall
authors.forename: Michael P
authors.initials: MP
authors.lastname: Winters
authors.forename: Ning
authors.initials: N
authors.lastname: Qin
authors.forename: Mary Lou
authors.initials: ML
authors.lastname: Lubin
authors.forename: Michael F A
authors.initials: MF
authors.lastname: Finley
authors.forename: Michael R
authors.initials: MR
authors.lastname: Brandt
authors.forename: Michael P
authors.initials: MP
authors.lastname: Neeper
authors.forename: Craig R
authors.initials: CR
authors.lastname: Schneider
authors.forename: Raymond W
authors.initials: RW
authors.lastname: Colburn
authors.forename: Christopher M
authors.initials: CM
authors.lastname: Flores
authors.forename: Zhihua
authors.initials: Z
authors.lastname: Sui
mesh_terms: D000700:Analgesics / Q000138:chemical synthesis* / Q000627:therapeutic use; D000818:Animals; D002121:Calcium Channel Blockers / Q000138:chemical synthesis* / Q000627:therapeutic use; D020864:Calcium Channels, N-Type / Q000378:metabolism*; D002460:Cell Line; D059350:Chronic Pain / Q000188:drug therapy* / Q000378:metabolism; D057166:High-Throughput Screening Assays; D006801:Humans; D009437:Neuralgia / Q000188:drug therapy* / Q000378:metabolism; D018408:Patch-Clamp Techniques; D010880:Piperidines / Q000138:chemical synthesis* / Q000627:therapeutic use; D011720:Pyrazoles / Q000138:chemical synthesis* / Q000627:therapeutic use; D051381:Rats; D013329:Structure-Activity Relationship; D020960:omega-Conotoxins / Q000627:therapeutic use
chemical_list: D000700:Analgesics; D002121:Calcium Channel Blockers; D020864:Calcium Channels, N-Type; D010880:Piperidines; D011720:Pyrazoles; D020960:omega-Conotoxins; C078452:ziconotide