Discovery and hit-to-lead optimization of pyrrolopyrimidines as potent, state-dependent Na(v)1.7 antagonists.
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.
Department of Chemistry Research and Discovery, Amgen Inc., 360 Binney St., Cambridge, MA 02142, USA. nchakka@amgen.com
Nagasree
N
Chakka
Howie
H
Bregman
Bingfan
B
Du
Hanh Nho
HN
Nguyen
John L
JL
Buchanan
Elma
E
Feric
Joseph
J
Ligutti
Dong
D
Liu
Jeff S
JS
McDermott
Anruo
A
Zou
Stefan I
SI
McDonough
Erin F
EF
Dimauro
D055808:Drug Discovery; D006801:Humans; D008862:Microsomes, Liver / Q000378:metabolism; D062556:NAV1.7 Voltage-Gated Sodium Channel; D010146:Pain / Q000188:drug therapy; D011743:Pyrimidines / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D011758:Pyrroles / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D026941:Sodium Channel Blockers / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D015222:Sodium Channels / Q000378:metabolism*; D013329:Structure-Activity Relationship
D062556:NAV1.7 Voltage-Gated Sodium Channel; D011743:Pyrimidines; D011758:Pyrroles; C486866:SCN9A protein, human; D026941:Sodium Channel Blockers; D015222:Sodium Channels; C527741:pyrrolopyrimidine