The discovery of aminopyrazines as novel, potent Na(v)1.7 antagonists: hit-to-lead identification and SAR.
Herein the discovery of a novel class of aminoheterocyclic Na(v)1.7 antagonists is reported. Hit compound 1 was potent but suffered from poor pharmacokinetics and selectivity. The compact structure of 1 offered a modular synthetic strategy towards a broad structure-activity relationship analysis. This analysis led to the identification of aminopyrazine 41, which had vastly improved hERG selectivity and pharmacokinetic properties.
Department of Chemistry Research and Discovery, Amgen Inc., 360 Binney St., Cambridge, MA 02142, USA. hbregman@amgen.com
Howard
H
Bregman
Hanh Nho
HN
Nguyen
Elma
E
Feric
Joseph
J
Ligutti
Dong
D
Liu
Jeff S
JS
McDermott
Ben
B
Wilenkin
Anruo
A
Zou
Liyue
L
Huang
Xingwen
X
Li
Stefan I
SI
McDonough
Erin F
EF
Dimauro
D000588:Amines / Q000737:chemistry / Q000378:metabolism / Q000493:pharmacokinetics / Q000494:pharmacology; D000818:Animals; D055808:Drug Discovery; D020128:Inhibitory Concentration 50; D008297:Male; D062556:NAV1.7 Voltage-Gated Sodium Channel; D010949:Plasma / Q000378:metabolism; D011719:Pyrazines / Q000737:chemistry* / Q000378:metabolism / Q000493:pharmacokinetics / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D026941:Sodium Channel Blockers / Q000737:chemistry* / Q000378:metabolism / Q000493:pharmacokinetics / Q000494:pharmacology*; D015222:Sodium Channels / Q000378:metabolism*; D013329:Structure-Activity Relationship
D000588:Amines; D062556:NAV1.7 Voltage-Gated Sodium Channel; D011719:Pyrazines; C486866:SCN9A protein, human; D026941:Sodium Channel Blockers; D015222:Sodium Channels