title: Synthesis and pharmacological evaluation of 1-alkyl-N-[2-ethyl-2-(4-fluorophenyl)butyl]piperidine-4-carboxamide derivatives as novel antihypertensive agents.
abstract: We synthesized and evaluated inhibitory activity against T-type Ca(2+) channels for a series of 1-alkyl-N-[2-ethyl-2-(4-fluorophenyl)butyl]piperidine-4-carboxamide derivatives. Structure-activity relationship studies have revealed that dialkyl substituents at the benzylic position play an important role in increasing inhibitory activity. Oral administration of N-[2-ethyl-2-(4-fluorophenyl)butyl]-1-(2-phenylethyl)piperidine-4-carboxamide (20d) lowered blood pressure in spontaneously hypertensive rats without inducing reflex tachycardia, which is often caused by traditional L-type Ca(2+) channel blockers.
authors.affiliation: Drug Discovery Research, Astellas Pharma Inc., 21 Miyukigaoka, Tsukuba, Ibaraki 305-8585, Japan. susumu.watanuki@jp.astellas.com
authors.forename: Susumu
authors.initials: S
authors.lastname: Watanuki
authors.forename: Keisuke
authors.initials: K
authors.lastname: Matsuura
authors.forename: Yuichi
authors.initials: Y
authors.lastname: Tomura
authors.forename: Minoru
authors.initials: M
authors.lastname: Okada
authors.forename: Toshio
authors.initials: T
authors.lastname: Okazaki
authors.forename: Mitsuaki
authors.initials: M
authors.lastname: Ohta
authors.forename: Shin-Ichi
authors.initials: S
authors.lastname: Tsukamoto
mesh_terms: D000818:Animals; D000959:Antihypertensive Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D016280:Atrial Function, Right / Q000187:drug effects; D001794:Blood Pressure / Q000187:drug effects; D020747:Calcium Channels, T-Type / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D006168:Guinea Pigs; D008297:Male; D015394:Molecular Structure; D010880:Piperidines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D051381:Rats; D011918:Rats, Inbred SHR; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013997:Time Factors
chemical_list: D000959:Antihypertensive Agents; D020747:Calcium Channels, T-Type; D010880:Piperidines