title: Application of a Parallel Synthetic Strategy in the Discovery of Biaryl Acyl Sulfonamides as Efficient and Selective NaV1.7 Inhibitors.
abstract: The majority of potent and selective hNaV1.7 inhibitors possess common pharmacophoric features that include a heteroaryl sulfonamide headgroup and a lipophilic aromatic tail group. Recently, reports of similar aromatic tail groups in combination with an acyl sulfonamide headgroup have emerged, with the acyl sulfonamide bestowing levels of selectivity over hNaV1.5 comparable to the heteroaryl sulfonamide. Beginning with commercially available carboxylic acids that met selected pharmacophoric requirements in the lipophilic tail, a parallel synthetic approach was applied to rapidly generate the derived acyl sulfonamides. A biaryl acyl sulfonamide hit from this library was elaborated, optimizing for potency and selectivity with attention to physicochemical properties. The resulting novel leads are potent, ligand and lipophilic efficient, and selective over hNaV1.5. Representative lead 36 demonstrates selectivity over other human NaV isoforms and good pharmacokinetics in rodents. The biaryl acyl sulfonamides reported herein may also offer ADME advantages over known heteroaryl sulfonamide inhibitors.
authors.forename: Erin F
authors.initials: EF
authors.lastname: DiMauro
authors.forename: Stephen
authors.initials: S
authors.lastname: Altmann
authors.forename: Loren M
authors.initials: LM
authors.lastname: Berry
authors.forename: Howard
authors.initials: H
authors.lastname: Bregman
authors.forename: Nagasree
authors.initials: N
authors.lastname: Chakka
authors.forename: Margaret
authors.initials: M
authors.lastname: Chu-Moyer
authors.forename: Elma Feric
authors.initials: EF
authors.lastname: Bojic
authors.forename: Robert S
authors.initials: RS
authors.lastname: Foti
authors.affiliation: Department of Neuroscience, Amgen Inc. , One Amgen Center Drive, Thousand Oaks, California 91320, United States.
authors.forename: Robert
authors.initials: R
authors.lastname: Fremeau
authors.forename: Hua
authors.initials: H
authors.lastname: Gao
authors.forename: Hakan
authors.initials: H
authors.lastname: Gunaydin
authors.forename: Angel
authors.initials: A
authors.lastname: Guzman-Perez
authors.forename: Brian E
authors.initials: BE
authors.lastname: Hall
authors.forename: Hongbing
authors.initials: H
authors.lastname: Huang
authors.forename: Michael
authors.initials: M
authors.lastname: Jarosh
authors.affiliation: Department of Neuroscience, Amgen Inc. , One Amgen Center Drive, Thousand Oaks, California 91320, United States.
authors.forename: Thomas
authors.initials: T
authors.lastname: Kornecook
authors.forename: Josie
authors.initials: J
authors.lastname: Lee
authors.affiliation: Department of Neuroscience, Amgen Inc. , One Amgen Center Drive, Thousand Oaks, California 91320, United States.
authors.forename: Joseph
authors.initials: J
authors.lastname: Ligutti
authors.affiliation: Department of Neuroscience, Amgen Inc. , One Amgen Center Drive, Thousand Oaks, California 91320, United States.
authors.forename: Dong
authors.initials: D
authors.lastname: Liu
authors.affiliation: Department of Neuroscience, Amgen Inc. , One Amgen Center Drive, Thousand Oaks, California 91320, United States.
authors.forename: Bryan D
authors.initials: BD
authors.lastname: Moyer
authors.forename: Daniel
authors.initials: D
authors.lastname: Ortuno
authors.forename: Paul E
authors.initials: PE
authors.lastname: Rose
authors.forename: Laurie B
authors.initials: LB
authors.lastname: Schenkel
authors.forename: Kristin
authors.initials: K
authors.lastname: Taborn
authors.forename: Jean
authors.initials: J
authors.lastname: Wang
authors.forename: Yan
authors.initials: Y
authors.lastname: Wang
authors.forename: Violeta
authors.initials: V
authors.lastname: Yu
authors.forename: Matthew M
authors.initials: MM
authors.lastname: Weiss
mesh_terms: D000818:Animals; D001549:Benzamides / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology; D002460:Cell Line; D005260:Female; D006632:Histamine; D006801:Humans; D008297:Male; D008810:Mice, Inbred C57BL; D008862:Microsomes, Liver / Q000378:metabolism; D062105:Molecular Docking Simulation; D062556:NAV1.7 Voltage-Gated Sodium Channel / Q000378:metabolism*; D011537:Pruritus / Q000139:chemically induced / Q000188:drug therapy; D011869:Radioligand Assay; D051381:Rats; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology; D061567:Voltage-Gated Sodium Channel Blockers / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology
chemical_list: C000621121:4-(5-chloro-6-(2,5-difluorophenoxy)-3-pyridinyl)-2-fluoro-5-methoxy-N-(methylsulfonyl)benzamide; D001549:Benzamides; D062556:NAV1.7 Voltage-Gated Sodium Channel; C486866:SCN9A protein, human; D013449:Sulfonamides; D061567:Voltage-Gated Sodium Channel Blockers; D006632:Histamine