title: Synthesis and pharmacological evaluation of 1-alkyl-N-[(1R)-1-(4-fluorophenyl)-2-methylpropyl]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-[(1R)-1-(4-fluorophenyl)-2-methylpropyl]piperidine-4-carboxamide derivatives. Structure-activity relationship studies have revealed that the isopropyl substituent at the benzylic position plays an important role in exerting potent inhibitory activity, and the absolute configuration of the benzylic position was found to be opposite that of mibefradil, which was first launched as a new class of T-type Ca(2+) channel blocker. Oral administration of N-[(1R)-1-(4-fluorophenyl)-2-methylpropyl]-1-[2-(3-methoxyphenyl)ethyl]piperidine-4-carboxamide (17f) lowered blood pressure in spontaneously hypertensive rats without inducing reflex tachycardia, an adverse effect often caused by traditional L-type Ca(2+) channel blockers.
authors: Drug Discovery Research, Astellas Pharma Inc., Tsukuba, Ibaraki 305–8585, Japan. susumu.watanuki@jp.astellas.com
authors: Susumu
authors: S
authors: Watanuki
authors: Keisuke
authors: K
authors: Matsuura
authors: Yuichi
authors: Y
authors: Tomura
authors: Minoru
authors: M
authors: Okada
authors: Toshio
authors: T
authors: Okazaki
authors: Mitsuaki
authors: M
authors: Ohta
authors: Shin-ichi
authors: S
authors: Tsukamoto
mesh_terms: D000577:Amides / Q000737:chemistry* / Q000494:pharmacology / Q000627:therapeutic use; D000818:Animals; D000959:Antihypertensive Agents / Q000138:chemical synthesis / Q000494:pharmacology* / Q000627:therapeutic use; D001794:Blood Pressure / Q000187:drug effects*; D002121:Calcium Channel Blockers / Q000138:chemical synthesis / Q000494:pharmacology* / Q000627:therapeutic use; D020747:Calcium Channels, T-Type / Q000737:chemistry / Q000378:metabolism; D002460:Cell Line; D006168:Guinea Pigs; D006801:Humans; D006973:Hypertension / Q000188:drug therapy; D008297:Male; D010880:Piperidines / Q000737:chemistry*; D051381:Rats; D011918:Rats, Inbred SHR; D013329:Structure-Activity Relationship
chemical_list: D000577:Amides; D000959:Antihypertensive Agents; D002121:Calcium Channel Blockers; D020747:Calcium Channels, T-Type; D010880:Piperidines; C032727:piperidine