Sulfonamides as Selective NaV1.7 Inhibitors: Optimizing Potency, Pharmacokinetics, and Metabolic Properties to Obtain Atropisomeric Quinolinone (AM-0466) that Affords Robust in Vivo Activity.
Because of its strong genetic validation, NaV1.7 has attracted significant interest as a target for the treatment of pain. We have previously reported on a number of structurally distinct bicyclic heteroarylsulfonamides as NaV1.7 inhibitors that demonstrate high levels of selectivity over other NaVisoforms. Herein, we report the discovery and optimization of a series of atropisomeric quinolinone sulfonamide inhibitors [ Bicyclic sulfonamide compounds as sodium channel inhibitors and their preparation . WO 2014201206, 2014 ] of NaV1.7, which demonstrate nanomolar inhibition of NaV1.7 and exhibit high levels of selectivity over other sodium channel isoforms. After optimization of metabolic and pharmacokinetic properties, including PXR activation, CYP2C9 inhibition, and CYP3A4 TDI, several compounds were advanced into in vivo target engagement and efficacy models. When tested in mice, compound 39 (AM-0466) demonstrated robust pharmacodynamic activity in a NaV1.7-dependent model of histamine-induced pruritus (itch) and additionally in a capsaicin-induced nociception model of pain without any confounding effect in open-field activity.
Russell F
0000-0001-8576-4832
RF
Graceffa
Alessandro A
AA
Boezio
Department of Neuroscience, Amgen Inc. , One Amgen Center Drive, Thousand Oaks, California 91320, United States.
Jessica
J
Able
Steven
S
Altmann
Loren M
LM
Berry
Christiane
C
Boezio
John R
JR
Butler
Margaret
M
Chu-Moyer
Melanie
M
Cooke
Erin F
EF
DiMauro
Thomas A
TA
Dineen
Elma
E
Feric Bojic
Robert S
RS
Foti
Robert T
RT
Fremeau
Angel
A
Guzman-Perez
Hua
H
Gao
Hakan
H
Gunaydin
Hongbing
H
Huang
Liyue
L
Huang
Christopher
C
Ilch
Michael
M
Jarosh
Department of Neuroscience, Amgen Inc. , One Amgen Center Drive, Thousand Oaks, California 91320, United States.
Thomas
T
Kornecook
Charles R
CR
Kreiman
Daniel S
DS
La
Department of Neuroscience, Amgen Inc. , One Amgen Center Drive, Thousand Oaks, California 91320, United States.
Joseph
J
Ligutti
Benjamin C
BC
Milgram
Min-Hwa Jasmine
MJ
Lin
Isaac E
0000-0003-2393-5768
IE
Marx
Hanh N
HN
Nguyen
Emily A
EA
Peterson
Gwen
G
Rescourio
John
J
Roberts
Laurie
L
Schenkel
Roman
R
Shimanovich
Brian A
BA
Sparling
John
J
Stellwagen
Kristin
K
Taborn
Karina R
KR
Vaida
Jean
J
Wang
John
J
Yeoman
Violeta
V
Yu
Dawn
D
Zhu
Department of Neuroscience, Amgen Inc. , One Amgen Center Drive, Thousand Oaks, California 91320, United States.
Bryan D
BD
Moyer
Matthew M
0000-0002-2559-2183
MM
Weiss
D000700:Analgesics / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D000818:Animals; D002211:Capsaicin; D002460:Cell Line; D004285:Dogs; D006632:Histamine; D008810:Mice, Inbred C57BL; D062105:Molecular Docking Simulation; D062556:NAV1.7 Voltage-Gated Sodium Channel / Q000378:metabolism*; D010146:Pain / Q000139:chemically induced / Q000517:prevention & control; D020033:Protein Isoforms / Q000037:antagonists & inhibitors / Q000378:metabolism; D011537:Pruritus / Q000139:chemically induced / Q000517:prevention & control; D015363:Quinolones / Q000008:administration & dosage / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology; D051381:Rats; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000008:administration & dosage / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology; D061567:Voltage-Gated Sodium Channel Blockers / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology
C000622274:AM-0466; D000700:Analgesics; D062556:NAV1.7 Voltage-Gated Sodium Channel; D020033:Protein Isoforms; D015363:Quinolones; D013449:Sulfonamides; D061567:Voltage-Gated Sodium Channel Blockers; D006632:Histamine; D002211:Capsaicin