title: Long-acting dihydropyridine calcium antagonists. 6. Structure-activity relationships around 4-(2,3-dichlorophenyl)-3-(ethoxycarbonyl)-2-[(2-hydroxyethoxy)methyl]-5 -(methoxycarbonyl)-6-methyl-1,4-dihydropyridine.
abstract: The preparation of 4-(2,3-dichlorophenyl)-3-(ethoxycarbonyl)-2-[(2-hydroxyethoxy)methyl]-5- (methoxycarbonyl)-6-methyl-1,4-dihydropyridine (2) is described, and its potent calcium antagonist activity on rat aorta (IC50 = 4 x 10(-9) M) and marked tissue selectivity in vitro for vascular smooth muscle over cardiac smooth muscle are established. In order to exploit the excellent in vitro profile of compound 2, a range of analogues were prepared but none were found to have superior calcium antagonist potency and tissue selectivity. Compound 2 has excellent in vivo activity in the anesthetized dog (ED50 = 12 micrograms/kg for reduction of CVR) and a plasma half-life in the conscious dog of 7.2 h. The pharmacokinetic parameters of 2 are compared to those determined for the structurally related compounds amlodipine and felodipine. The plasma clearance for 2 (9.6 mL/min/kg) is similar to that of amlodipine and is consistent with the extended 2-substituent hindering approach to the cytochrome P-450 enzyme responsible for oxidation of the DHP ring to the corresponding pyridine.
authors.affiliation: Pfizer Central Research, Sandwich, Kent, United Kingdom.
authors.forename: D
authors.initials: D
authors.lastname: Alker
authors.forename: S F
authors.initials: SF
authors.lastname: Campbell
authors.forename: P E
authors.initials: PE
authors.lastname: Cross
mesh_terms: D000818:Animals; D002121:Calcium Channel Blockers / Q000138:chemical synthesis*; D004095:Dihydropyridines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D004285:Dogs; D006339:Heart Rate / Q000187:drug effects; D007202:Indicators and Reagents; D009682:Magnetic Resonance Spectroscopy; D015394:Molecular Structure; D013329:Structure-Activity Relationship
chemical_list: D002121:Calcium Channel Blockers; D004095:Dihydropyridines; D007202:Indicators and Reagents; C067051:4-(2,3-dichlorophenyl)-3-(ethoxycarbonyl)-2-((2-hydroxyethoxy)methyl)-5-(methoxycarbonyl)-6-methyl-1,4-dihydropyridine