title: Sulfonamides as Selective NaV1.7 Inhibitors: Optimizing Potency and Pharmacokinetics While Mitigating Metabolic Liabilities.
abstract: Several reports have recently emerged regarding the identification of heteroarylsulfonamides as NaV1.7 inhibitors that demonstrate high levels of selectivity over other NaVisoforms. The optimization of a series of internal NaV1.7 leads that address a number of metabolic liabilities including bioactivation, PXR activation, as well as CYP3A4 induction and inhibition led to the identification of potent and selective inhibitors that demonstrated favorable pharmacokinetic profiles and were devoid of the aforementioned liabilities. The key to achieving this within a series prone to transporter-mediated clearance was the identification of a small range of optimal cLogD values and the discovery of subtle PXR SAR that was not lipophilicity dependent. This enabled the identification of compound 20, which was advanced into a target engagement pharmacodynamic model where it exhibited robust reversal of histamine-induced scratching bouts in mice.
authors.forename: Matthew M
authors.identifier: 0000-0002-2559-2183
authors.initials: MM
authors.lastname: Weiss
authors.forename: Thomas A
authors.initials: TA
authors.lastname: Dineen
authors.forename: Isaac E
authors.identifier: 0000-0003-2393-5768
authors.initials: IE
authors.lastname: Marx
authors.forename: Steven
authors.initials: S
authors.lastname: Altmann
authors.forename: Alessandro
authors.initials: A
authors.lastname: Boezio
authors.forename: Howard
authors.identifier: 0000-0001-8062-9770
authors.initials: H
authors.lastname: Bregman
authors.forename: Margaret
authors.initials: M
authors.lastname: Chu-Moyer
authors.forename: Erin F
authors.initials: EF
authors.lastname: DiMauro
authors.forename: Elma
authors.initials: E
authors.lastname: Feric Bojic
authors.forename: Robert S
authors.initials: RS
authors.lastname: Foti
authors.forename: Hua
authors.initials: H
authors.lastname: Gao
authors.forename: Russell
authors.identifier: 0000-0001-8576-4832
authors.initials: R
authors.lastname: Graceffa
authors.forename: Hakan
authors.initials: H
authors.lastname: Gunaydin
authors.forename: Angel
authors.initials: A
authors.lastname: Guzman-Perez
authors.forename: Hongbing
authors.initials: H
authors.lastname: Huang
authors.forename: Liyue
authors.initials: L
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: Charles R
authors.initials: CR
authors.lastname: Kreiman
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.forename: Daniel S
authors.initials: DS
authors.lastname: La
authors.forename: Min-Hwa Jasmine
authors.initials: MJ
authors.lastname: Lin
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: Hanh N
authors.initials: HN
authors.lastname: Nguyen
authors.forename: Emily A
authors.initials: EA
authors.lastname: Peterson
authors.forename: Paul E
authors.initials: PE
authors.lastname: Rose
authors.forename: Kristin
authors.initials: K
authors.lastname: Taborn
authors.forename: Beth D
authors.initials: BD
authors.lastname: Youngblood
authors.forename: Violeta
authors.initials: V
authors.lastname: Yu
authors.forename: Robert T
authors.initials: RT
authors.lastname: Fremeau
mesh_terms: D000818:Animals; D002460:Cell Line; D051544:Cytochrome P-450 CYP3A / Q000096:biosynthesis; D065692:Cytochrome P-450 CYP3A Inhibitors / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D004285:Dogs; D004790:Enzyme Induction; D006632:Histamine; D006801:Humans; D007546:Isoquinolines / Q000008:administration & dosage / Q000737:chemistry* / Q000493:pharmacokinetics; D008297:Male; D008810:Mice, Inbred C57BL; D062556:NAV1.7 Voltage-Gated Sodium Channel / Q000378:metabolism*; D000077297:Pregnane X Receptor; D011537:Pruritus / Q000139:chemically induced / Q000517:prevention & control; D051381:Rats; D011987:Receptors, Steroid / Q000819:agonists; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000008:administration & dosage / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology; D061567:Voltage-Gated Sodium Channel Blockers / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology
chemical_list: C000622273:1-(2-fluoro-5-methoxy-3'-(trifluoromethyl)-(1,1'-biphenyl)-4-yl)-N-(isoxazol-3-yl)isoquinoline-6-sulfonamide; D065692:Cytochrome P-450 CYP3A Inhibitors; D007546:Isoquinolines; D062556:NAV1.7 Voltage-Gated Sodium Channel; D000077297:Pregnane X Receptor; D011987:Receptors, Steroid; D013449:Sulfonamides; D061567:Voltage-Gated Sodium Channel Blockers; D006632:Histamine; D051544:Cytochrome P-450 CYP3A