title: Design, synthesis and evaluation of phenethylaminoheterocycles as K(v)1.5 inhibitors.
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.
authors.affiliation: Department of Discovery Chemistry, Bristol-Myers Squibb Research and Development, PO Box 5400, Princeton, NJ 08534-5400, USA. Electronic address: james.a.johnson@bms.com.
authors.forename: James A
authors.initials: JA
authors.lastname: Johnson
authors.affiliation: Department of Discovery Chemistry, Bristol-Myers Squibb Research and Development, PO Box 5400, Princeton, NJ 08534-5400, USA.
authors.forename: Ningning
authors.initials: N
authors.lastname: Xu
authors.affiliation: Department of Discovery Chemistry, Bristol-Myers Squibb Research and Development, PO Box 5400, Princeton, NJ 08534-5400, USA.
authors.forename: Yoon
authors.initials: Y
authors.lastname: Jeon
authors.affiliation: Department of Discovery Chemistry, Bristol-Myers Squibb Research and Development, PO Box 5400, Princeton, NJ 08534-5400, USA.
authors.forename: Heather J
authors.initials: HJ
authors.lastname: Finlay
authors.affiliation: Department of Discovery Chemistry, Bristol-Myers Squibb Research and Development, PO Box 5400, Princeton, NJ 08534-5400, USA.
authors.forename: Alexander
authors.initials: A
authors.lastname: Kover
authors.affiliation: Department of Discovery Biology, Bristol-Myers Squibb Research and Development, PO Box 5400, Princeton, NJ 08534-5400, USA.
authors.forename: Mary L
authors.initials: ML
authors.lastname: Conder
authors.affiliation: Department of Discovery Biology, Bristol-Myers Squibb Research and Development, PO Box 5400, Princeton, NJ 08534-5400, USA.
authors.forename: Huabin
authors.initials: H
authors.lastname: Sun
authors.affiliation: Department of Discovery Biology, Bristol-Myers Squibb Research and Development, PO Box 5400, Princeton, NJ 08534-5400, USA.
authors.forename: Danshi
authors.initials: D
authors.lastname: Li
authors.affiliation: Department of Discovery Biology, Bristol-Myers Squibb Research and Development, PO Box 5400, Princeton, NJ 08534-5400, USA.
authors.forename: Paul
authors.initials: P
authors.lastname: Levesque
authors.affiliation: Department of Preclinical Candidate Optimization, Bristol-Myers Squibb Research and Development, PO Box 5400, Princeton, NJ 08534-5400, USA.
authors.forename: Mei-Mann
authors.initials: MM
authors.lastname: Hsueh
authors.affiliation: Department of Preclinical Candidate Optimization, Bristol-Myers Squibb Research and Development, PO Box 5400, Princeton, NJ 08534-5400, USA.
authors.forename: Timothy W
authors.initials: TW
authors.lastname: Harper
authors.affiliation: Department of Discovery Chemistry, Bristol-Myers Squibb Research and Development, PO Box 5400, Princeton, NJ 08534-5400, USA.
authors.forename: Ruth R
authors.initials: RR
authors.lastname: Wexler
authors.affiliation: Department of Discovery Chemistry, Bristol-Myers Squibb Research and Development, PO Box 5400, Princeton, NJ 08534-5400, USA.
authors.forename: John
authors.initials: J
authors.lastname: Lloyd
mesh_terms: D000818:Animals; D002219:Carbamates / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D006325:Heart Atria / Q000187:drug effects; D006339:Heart Rate / Q000187:drug effects; D006801:Humans; D007191:Indazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D051666:Kv1.5 Potassium Channel / Q000037:antagonists & inhibitors*; D008958:Models, Molecular; D015394:Molecular Structure; D026902:Potassium Channel Blockers / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D011817:Rabbits; D051381:Rats; D013329:Structure-Activity Relationship
chemical_list: D002219:Carbamates; D007191:Indazoles; D051666:Kv1.5 Potassium Channel; D026902:Potassium Channel Blockers
keywords: AERP; Aminoheterocycle; Atrial fibrillation; I(Kur); K(v)1.5