Discovery and hit-to-lead evaluation of piperazine amides as selective, state-dependent NaV1.7 inhibitors

Brian A Sparling; S Yi; J Able; H Bregman; Erin F DiMauro; R S Foti; H Gao; A Guzman-Perez; H Huang; M Jarosh; T Kornecook; J Ligutti; B C Milgram; B D Moyer; B Youngblood; V L Yu; M M Weiss

doi:10.1039/c6md00578k

Discovery and hit-to-lead evaluation of piperazine amides as selective, state-dependent Na_V1.7 inhibitors

Medchemcomm. 2016 Dec 2;8(4):744-754. doi: 10.1039/c6md00578k. eCollection 2017 Apr 1.

Authors

Brian A Sparling¹, S Yi¹, J Able², H Bregman¹, Erin F DiMauro¹, R S Foti³, H Gao⁴, A Guzman-Perez¹, H Huang¹, M Jarosh⁵, T Kornecook², J Ligutti², B C Milgram¹, B D Moyer², B Youngblood², V L Yu⁵, M M Weiss¹

Affiliations

¹ Department of Medicinal Chemistry , Amgen Inc. , 360 Binney Street , Cambridge , MA 02142 , USA . Email: [email protected].
² Department of Neuroscience , Amgen Inc. , One Amgen Center Drive , Thousand Oaks , CA 91320 , USA.
³ Department of Pharmacokinetics and Drug Metabolism , Amgen Inc. , 360 Binney Street , Cambridge , MA 02142 , USA.
⁴ Department of Molecular Engineering, Amgen Inc. , 360 Binney Street , Cambridge , MA 02142 , USA.
⁵ Department of Neuroscience , Amgen Inc. , 360 Binney Street , Cambridge , MA 02142 , USA.

Abstract

Na_V1.7 is a particularly compelling target for the treatment of pain. Herein, we report the discovery and evaluation of a series of piperazine amides that exhibit state-dependent inhibition of Na_V1.7. After demonstrating significant pharmacodynamic activity with early lead compound 14 in a Na_V1.7-dependent behavioural mouse model, we systematically established SAR trends throughout each sector of the scaffold. The information gleaned from this modular analysis was then applied additively to quickly access analogues that encompass an optimal balance of properties, including Na_V1.7 potency, selectivity over Na_V1.5, aqueous solubility, and microsomal stability.