Discovery and hit-to-lead optimization of pyrrolopyrimidines as potent, state-dependent Na(v)1.7 antagonists

Nagasree Chakka; Howie Bregman; Bingfan Du; Hanh Nho Nguyen; John L Buchanan; Elma Feric; Joseph Ligutti; Dong Liu; Jeff S McDermott; Anruo Zou; Stefan I McDonough; Erin F Dimauro

doi:10.1016/j.bmcl.2012.01.015

Discovery and hit-to-lead optimization of pyrrolopyrimidines as potent, state-dependent Na(v)1.7 antagonists

Bioorg Med Chem Lett. 2012 Mar 1;22(5):2052-62. doi: 10.1016/j.bmcl.2012.01.015. Epub 2012 Jan 18.

Authors

Nagasree Chakka¹, Howie Bregman, Bingfan Du, Hanh Nho Nguyen, John L Buchanan, Elma Feric, Joseph Ligutti, Dong Liu, Jeff S McDermott, Anruo Zou, Stefan I McDonough, Erin F Dimauro

Affiliation

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

PMID: 22318156
DOI: 10.1016/j.bmcl.2012.01.015

Abstract

Herein we describe the discovery, optimization, and structure-activity relationships of novel potent pyrrolopyrimidine Na(v)1.7 antagonists. Hit-to-lead SAR studies of the pyrrolopyrimidine core, head, and tail groups of the molecule led to the identification of pyrrolopyrimidine 48 as exceptionally potent Na(v)1.7 blocker with good selectivity over hERG and improved microsomal stability relative to our hit molecule and pyrazolopyrimidine 8 as a promising starting point for future optimization efforts.

MeSH terms

Drug Discovery
Humans
Microsomes, Liver / metabolism
NAV1.7 Voltage-Gated Sodium Channel
Pain / drug therapy
Pyrimidines / chemistry*
Pyrimidines / metabolism
Pyrimidines / pharmacology*
Pyrroles / chemistry*
Pyrroles / metabolism
Pyrroles / pharmacology*
Sodium Channel Blockers / chemistry*
Sodium Channel Blockers / metabolism
Sodium Channel Blockers / pharmacology*
Sodium Channels / metabolism*
Structure-Activity Relationship

Substances

NAV1.7 Voltage-Gated Sodium Channel
Pyrimidines
Pyrroles
SCN9A protein, human
Sodium Channel Blockers
Sodium Channels
pyrrolopyrimidine