title: 2-(2-Aryl-2-oxoethylidene)-1,2,3,4-tetrahydropyridines. Novel isomers of 1,4-dihydropyridine calcium channel blockers.
abstract: The title compounds are novel double bond isomers of 1,4-dihydropyridine-type calcium channel blockers (CCB). These derivatives were prepared by using the Hantzsch dihydropyridine synthesis. The assignment of structure was based on spectroscopic data and a regiochemically unambiguous synthesis. Several of the analogues inhibited [3H]nitrendipine binding with IC50 values as low as 25 nM. By comparison, nifedipine, a clinically useful 1,4-dihydropyridine CCB, inhibits [3H]nitrendipine binding with an IC50 of 1.6 nM. In the Langendorff rat heart preparation, treatment with the more potent derivatives produced marked dose-related increases in coronary flow with little or no effect on heart rate or contractility, except at the highest concentrations tested. The selectivity for vascular versus cardiac effects was similar to that of nifedipine, i.e., the concentration producing vasodilation was approximately 2 orders of magnitude lower than the concentration eliciting cardiodepression. These novel isomers extend the structure-activity relationships for calcium channel blockers into a series closely related to the 1,4-dihydropyridines.
authors.affiliation: Department of Chemistry, Parke-Davis Pharmaceutical Research, Division of Warner-Lambert Company, Ann Arbor, Michigan 48105.
authors.forename: M D
authors.initials: MD
authors.lastname: Taylor
authors.forename: E W
authors.initials: EW
authors.lastname: Badger
authors.forename: R P
authors.initials: RP
authors.lastname: Steffen
authors.forename: S J
authors.initials: SJ
authors.lastname: Haleen
authors.forename: T A
authors.initials: TA
authors.lastname: Pugsley
authors.forename: Y H
authors.initials: YH
authors.lastname: Shih
authors.forename: R E
authors.initials: RE
authors.lastname: Weishaar
mesh_terms: D000818:Animals; D001921:Brain / Q000187:drug effects; D002121:Calcium Channel Blockers / Q000138:chemical synthesis*; D015220:Calcium Channels; D003331:Coronary Vessels / Q000187:drug effects; D006321:Heart / Q000187:drug effects; D066298:In Vitro Techniques; D007536:Isomerism; D009543:Nifedipine / Q000494:pharmacology; D009568:Nitrendipine / Q000378:metabolism; D011725:Pyridines / Q000138:chemical synthesis* / Q000494:pharmacology; D011817:Rabbits; D051381:Rats; D011978:Receptors, Nicotinic / Q000187:drug effects; D013329:Structure-Activity Relationship
chemical_list: D002121:Calcium Channel Blockers; D015220:Calcium Channels; D011725:Pyridines; D011978:Receptors, Nicotinic; D009568:Nitrendipine; D009543:Nifedipine