The discovery of aminopyrazines as novel, potent Na(v)1.7 antagonists: hit-to-lead identification and SAR

Howard Bregman; Hanh Nho Nguyen; Elma Feric; Joseph Ligutti; Dong Liu; Jeff S McDermott; Ben Wilenkin; Anruo Zou; Liyue Huang; Xingwen Li; Stefan I McDonough; Erin F Dimauro

doi:10.1016/j.bmcl.2012.01.023

The discovery of aminopyrazines as novel, potent Na(v)1.7 antagonists: hit-to-lead identification and SAR

Bioorg Med Chem Lett. 2012 Mar 1;22(5):2033-42. doi: 10.1016/j.bmcl.2012.01.023. Epub 2012 Jan 18.

Authors

Howard Bregman¹, Hanh Nho Nguyen, Elma Feric, Joseph Ligutti, Dong Liu, Jeff S McDermott, Ben Wilenkin, Anruo Zou, Liyue Huang, Xingwen Li, Stefan I McDonough, Erin F Dimauro

Affiliation

¹ Department of Chemistry Research and Discovery, Amgen Inc., 360 Binney St., Cambridge, MA 02142, USA. hbregman@amgen.com

PMID: 22306122
DOI: 10.1016/j.bmcl.2012.01.023

Abstract

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.

MeSH terms

Amines / chemistry
Amines / metabolism
Amines / pharmacokinetics
Amines / pharmacology
Animals
Drug Discovery
Inhibitory Concentration 50
Male
NAV1.7 Voltage-Gated Sodium Channel
Plasma / metabolism
Pyrazines / chemistry*
Pyrazines / metabolism
Pyrazines / pharmacokinetics
Pyrazines / pharmacology*
Rats
Rats, Sprague-Dawley
Sodium Channel Blockers / chemistry*
Sodium Channel Blockers / metabolism
Sodium Channel Blockers / pharmacokinetics
Sodium Channel Blockers / pharmacology*
Sodium Channels / metabolism*
Structure-Activity Relationship

Substances

Amines
NAV1.7 Voltage-Gated Sodium Channel
Pyrazines
SCN9A protein, human
Sodium Channel Blockers
Sodium Channels