Design, synthesis and evaluation of phenethylaminoheterocycles as K(v)1.5 inhibitors

James A Johnson; Ningning Xu; Yoon Jeon; Heather J Finlay; Alexander Kover; Mary L Conder; Huabin Sun; Danshi Li; Paul Levesque; Mei-Mann Hsueh; Timothy W Harper; Ruth R Wexler; John Lloyd

doi:10.1016/j.bmcl.2014.05.035

Design, synthesis and evaluation of phenethylaminoheterocycles as K(v)1.5 inhibitors

Bioorg Med Chem Lett. 2014 Jul 15;24(14):3018-22. doi: 10.1016/j.bmcl.2014.05.035. Epub 2014 May 20.

Authors

Affiliations

¹ Department of Discovery Chemistry, Bristol-Myers Squibb Research and Development, PO Box 5400, Princeton, NJ 08534-5400, USA. Electronic address: [email protected].
² Department of Discovery Chemistry, Bristol-Myers Squibb Research and Development, PO Box 5400, Princeton, NJ 08534-5400, USA.
³ Department of Discovery Biology, Bristol-Myers Squibb Research and Development, PO Box 5400, Princeton, NJ 08534-5400, USA.
⁴ Department of Preclinical Candidate Optimization, Bristol-Myers Squibb Research and Development, PO Box 5400, Princeton, NJ 08534-5400, USA.

PMID: 24881565
DOI: 10.1016/j.bmcl.2014.05.035

Abstract

Phenethylaminoheterocycles have been prepared and assayed for inhibition of the Kv1.5 potassium ion channel as a potential approach to the treatment of atrial fibrillation. A diverse set of heterocycles were identified as potent Kv1.5 inhibitors and were advanced to pharmacodynamic evaluation based on selectivity and pharmacokinetic profile. Heterocycle optimization and template modification lead to the identification of compound 24 which demonstrated increased atrial effective refractory period in the rabbit pharmacodynamic model with mild effects on blood pressure and heart rate.

Keywords: AERP; Aminoheterocycle; Atrial fibrillation; I(Kur); K(v)1.5.

MeSH terms

Animals
Carbamates / chemical synthesis
Carbamates / chemistry
Carbamates / pharmacology*
Dose-Response Relationship, Drug
Drug Design*
Heart Atria / drug effects
Heart Rate / drug effects
Humans
Indazoles / chemical synthesis
Indazoles / chemistry
Indazoles / pharmacology*
Kv1.5 Potassium Channel / antagonists & inhibitors*
Models, Molecular
Molecular Structure
Potassium Channel Blockers / chemical synthesis
Potassium Channel Blockers / chemistry
Potassium Channel Blockers / pharmacology*
Rabbits
Rats
Structure-Activity Relationship

Substances

Carbamates
Indazoles
Kv1.5 Potassium Channel
Potassium Channel Blockers