Discovery and optimization of aminopyrimidinones as potent and state-dependent Nav1.7 antagonists.
Clinical genetic data have shown that the product of the SCN9A gene, voltage-gated sodium ion channel Nav1.7, is a key control point for pain perception and a possible target for a next generation of analgesics. Sodium channels, however, historically have been difficult drug targets, and many of the existing structure-activity relationships (SAR) have been defined on pharmacologically modified channels with indirect reporter assays. Herein we describe the discovery, optimization, and SAR of potent aminopyrimidinone Nav1.7 antagonists using electrophysiology-based assays that measure the ligand-receptor interaction directly. Within this series, rapid functionalization at the polysubstituted aminopyrimidinone head group enabled exploration of SAR and of pharmacokinetic properties. Lead optimized N-Me-aminopyrimidinone 9 exhibited improved Nav1.7 potency, minimal off-target hERG liability, and improved rat PK properties.
Department of Chemistry Research and Discovery, Amgen Inc., 360 Binney St., Cambridge, MA 02142, USA. hanhn@amgen.com
Hanh Nho
HN
Nguyen
Howie
H
Bregman
John L
JL
Buchanan
Bingfan
B
Du
Elma
E
Feric
Liyue
L
Huang
Xingwen
X
Li
Joseph
J
Ligutti
Dong
D
Liu
Annika B
AB
Malmberg
David J
DJ
Matson
Jeff S
JS
McDermott
Vinod F
VF
Patel
Ben
B
Wilenkin
Anruo
A
Zou
Stefan I
SI
McDonough
Erin F
EF
Dimauro
D000818:Animals; D004305:Dose-Response Relationship, Drug; D006801:Humans; D008024:Ligands; D008862:Microsomes, Liver / Q000378:metabolism; D015394:Molecular Structure; D062556:NAV1.7 Voltage-Gated Sodium Channel; D011744:Pyrimidinones / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D051381:Rats; D015222:Sodium Channels / Q000378:metabolism*; D013329:Structure-Activity Relationship
D008024:Ligands; D062556:NAV1.7 Voltage-Gated Sodium Channel; D011744:Pyrimidinones; C486866:SCN9A protein, human; D015222:Sodium Channels