Pyrrolidine amides of pyrazolodihydropyrimidines as potent and selective KV1.5 blockers

John Lloyd; Heather J Finlay; Wayne Vacarro; Tram Hyunh; Alexander Kover; Rao Bhandaru; Lin Yan; Karnail Atwal; Mary Lee Conder; Tonya Jenkins-West; Hong Shi; Christine Huang; Danshi Li; Huabin Sun; Paul Levesque

doi:10.1016/j.bmcl.2009.12.085

Pyrrolidine amides of pyrazolodihydropyrimidines as potent and selective KV1.5 blockers

Bioorg Med Chem Lett. 2010 Feb 15;20(4):1436-9. doi: 10.1016/j.bmcl.2009.12.085. Epub 2010 Jan 4.

Authors

John Lloyd¹, Heather J Finlay, Wayne Vacarro, Tram Hyunh, Alexander Kover, Rao Bhandaru, Lin Yan, Karnail Atwal, Mary Lee Conder, Tonya Jenkins-West, Hong Shi, Christine Huang, Danshi Li, Huabin Sun, Paul Levesque

Affiliation

¹ Bristol-Myers Squibb Pharmaceutical Research and Development, Princeton, NJ 08543, USA. john.lloyd@bms.com

PMID: 20097068
DOI: 10.1016/j.bmcl.2009.12.085

Abstract

Design and synthesis of pyrazolodihydropyrimidines as KV1.5 blockers led to the discovery of 7d as a potent and selective antagonist. This compound showed atrial selective prolongation of effective refractory period in rabbits and was selected for clinical development.

MeSH terms

Amides / chemical synthesis*
Amides / chemistry
Amides / pharmacology
Animals
Dogs
Dose-Response Relationship, Drug
Inhibitory Concentration 50
Kv1.5 Potassium Channel / antagonists & inhibitors*
Molecular Structure
Potassium Channel Blockers / chemical synthesis*
Potassium Channel Blockers / chemistry
Potassium Channel Blockers / pharmacology
Pyrazoles / pharmacology*
Pyrrolidines / chemical synthesis
Pyrrolidines / chemistry*
Pyrrolidines / pharmacology
Rabbits
Rats

Substances

Amides
Kv1.5 Potassium Channel
Potassium Channel Blockers
Pyrazoles
Pyrrolidines
pyrrolidine