title: Discovery of selective, orally bioavailable, N-linked arylsulfonamide Nav1.7 inhibitors with pain efficacy in mice.
abstract: The voltage-gated sodium channel Nav1.7 is a genetically validated target for the treatment of pain with gain-of-function mutations in man eliciting a variety of painful disorders and loss-of-function mutations affording insensitivity to pain. Unfortunately, drugs thought to garner efficacy via Nav1 inhibition have undesirable side effect profiles due to their lack of selectivity over channel isoforms. Herein we report the discovery of a novel series of orally bioavailable arylsulfonamide Nav1.7 inhibitors with high levels of selectivity over Nav1.5, the Navisoform responsible for cardiovascular side effects, through judicious use of parallel medicinal chemistry and physicochemical property optimization. This effort produced inhibitors such as compound 5 with excellent potency, selectivity, behavioral efficacy in a rodent pain model, and efficacy in a mouse itch model suggestive of target modulation.
authors.affiliation: Department of Discovery Chemistry Merck & Co., Inc., West Point, PA 19486, USA. Electronic address: anthony_roecker@merck.com.
authors.forename: Anthony J
authors.initials: AJ
authors.lastname: Roecker
authors.affiliation: Department of Discovery Chemistry Merck & Co., Inc., West Point, PA 19486, USA.
authors.forename: Melissa
authors.initials: M
authors.lastname: Egbertson
authors.affiliation: Department of Discovery Chemistry Merck & Co., Inc., West Point, PA 19486, USA.
authors.forename: Kristen L G
authors.initials: KLG
authors.lastname: Jones
authors.affiliation: Department of Discovery Chemistry Merck & Co., Inc., West Point, PA 19486, USA.
authors.forename: Robert
authors.initials: R
authors.lastname: Gomez
authors.affiliation: Department of Pharmacology Merck & Co., Inc., West Point, PA 19486, USA.
authors.forename: Richard L
authors.initials: RL
authors.lastname: Kraus
authors.affiliation: Department of Pharmacology Merck & Co., Inc., West Point, PA 19486, USA.
authors.forename: Yuxing
authors.initials: Y
authors.lastname: Li
authors.affiliation: Department of Pharmacology Merck & Co., Inc., West Point, PA 19486, USA.
authors.forename: Amy Jo
authors.initials: AJ
authors.lastname: Koser
authors.affiliation: Department of Pharmacology Merck & Co., Inc., West Point, PA 19486, USA.
authors.forename: Mark O
authors.initials: MO
authors.lastname: Urban
authors.affiliation: Department of Neuroscience Merck & Co., Inc., West Point, PA 19486, USA.
authors.forename: Rebecca
authors.initials: R
authors.lastname: Klein
authors.affiliation: Department of Neuroscience Merck & Co., Inc., West Point, PA 19486, USA.
authors.forename: Michelle
authors.initials: M
authors.lastname: Clements
authors.affiliation: Department of Neuroscience Merck & Co., Inc., West Point, PA 19486, USA.
authors.forename: Jacqueline
authors.initials: J
authors.lastname: Panigel
authors.affiliation: Department of Pharmacology Merck & Co., Inc., West Point, PA 19486, USA.
authors.forename: Christopher
authors.initials: C
authors.lastname: Daley
authors.affiliation: Department of Neuroscience Merck & Co., Inc., West Point, PA 19486, USA.
authors.forename: Jixin
authors.initials: J
authors.lastname: Wang
authors.affiliation: Department of Pharmacology Merck & Co., Inc., West Point, PA 19486, USA.
authors.forename: Eleftheria N
authors.initials: EN
authors.lastname: Finger
authors.affiliation: Department of Pharmacology Merck & Co., Inc., West Point, PA 19486, USA.
authors.forename: John
authors.initials: J
authors.lastname: Majercak
authors.affiliation: Department of Neuroscience Merck & Co., Inc., West Point, PA 19486, USA.
authors.forename: Vincent
authors.initials: V
authors.lastname: Santarelli
authors.affiliation: Department of Pharmacology Merck & Co., Inc., West Point, PA 19486, USA.
authors.forename: Irene
authors.initials: I
authors.lastname: Gregan
authors.affiliation: Department of Pharmacology Merck & Co., Inc., West Point, PA 19486, USA.
authors.forename: Matthew
authors.initials: M
authors.lastname: Cato
authors.affiliation: Department of Pharmacology Merck & Co., Inc., West Point, PA 19486, USA.
authors.forename: Tracey
authors.initials: T
authors.lastname: Filzen
authors.affiliation: Department of Pharmacology Merck & Co., Inc., West Point, PA 19486, USA.
authors.forename: Aneta
authors.initials: A
authors.lastname: Jovanovska
authors.affiliation: Department of Drug Metabolism Merck & Co., Inc., West Point, PA 19486, USA.
authors.forename: Ying-Hong
authors.initials: YH
authors.lastname: Wang
authors.affiliation: Department of Chemistry Modeling & Informatics Merck & Co., Inc., West Point, PA 19486, USA.
authors.forename: Deping
authors.initials: D
authors.lastname: Wang
authors.affiliation: Department of Analytical Chemistry Merck & Co., Inc., West Point, PA 19486, USA.
authors.forename: Leo A
authors.initials: LA
authors.lastname: Joyce
authors.affiliation: Department of Analytical Chemistry Merck & Co., Inc., West Point, PA 19486, USA.
authors.forename: Edward C
authors.initials: EC
authors.lastname: Sherer
authors.affiliation: WuXi AppTec Co., Ltd, Shanghai, China.
authors.forename: Xuanjia
authors.initials: X
authors.lastname: Peng
authors.affiliation: WuXi AppTec Co., Ltd, Shanghai, China.
authors.forename: Xiu
authors.initials: X
authors.lastname: Wang
authors.affiliation: WuXi AppTec Co., Ltd, Shanghai, China.
authors.forename: Haiyan
authors.initials: H
authors.lastname: Sun
authors.affiliation: Department of Discovery Chemistry Merck & Co., Inc., West Point, PA 19486, USA.
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Coleman
authors.affiliation: Department of Pharmacology Merck & Co., Inc., West Point, PA 19486, USA.
authors.forename: Andrea K
authors.initials: AK
authors.lastname: Houghton
authors.affiliation: Department of Discovery Chemistry Merck & Co., Inc., West Point, PA 19486, USA.
authors.forename: Mark E
authors.initials: ME
authors.lastname: Layton
mesh_terms: D000284:Administration, Oral; D000818:Animals; D004195:Disease Models, Animal; D004353:Drug Evaluation, Preclinical; D006207:Half-Life; D020128:Inhibitory Concentration 50; D051379:Mice; D062556:NAV1.7 Voltage-Gated Sodium Channel / Q000737:chemistry / Q000378:metabolism; D009584:Nitrogen / Q000737:chemistry; D010146:Pain / Q000188:drug therapy; D020033:Protein Isoforms / Q000037:antagonists & inhibitors / Q000378:metabolism; D051381:Rats; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000737:chemistry* / Q000493:pharmacokinetics / Q000627:therapeutic use; D061567:Voltage-Gated Sodium Channel Blockers / Q000737:chemistry* / Q000493:pharmacokinetics / Q000627:therapeutic use
chemical_list: D062556:NAV1.7 Voltage-Gated Sodium Channel; D020033:Protein Isoforms; D013449:Sulfonamides; D061567:Voltage-Gated Sodium Channel Blockers; D009584:Nitrogen
keywords: Arylsulfonamide; Ion channel; Na(v)1.7; Pain; Selectivity