Design and synthesis of alkyl 7,7-dihalo-3-methyl-5-(nitrophenyl)-2-azabicyclo[4.1.0]hept-3-ene-4-carboxylates with calcium channel antagonist activity.
A group of alkyl 7,7-dihalo-3-methyl-5-(2- or 3-nitrophenyl)-2-azabicyclo[4.1.0]hept-3-ene-4-carboxylates were prepared by reaction of dihalocarbenes (:CX(2), X=Br, Cl) with alkyl 2-methyl-4-(2- or 3-nitrophenyl)-1,4-dihydropyridine-3-carboxylates. In vitro calcium channel antagonist activities were determined using a guinea pig ileum longitudinal smooth muscle assay. The title compounds exhibited weaker CC antagonist activity (10(-5) to 10(-7)M range) than the reference drug nifedipine (1.4 x 10(-8)M). Structure-activity relationships showed that the position (ortho or meta) of the nitro-substituent on the C-5 phenyl ring, the size (van der Waal's radius for Br and Cl are 1.95 and 1.80A, respectively) and/or electronegativity (Cl>Br) of the C-7 geminal halogen atoms do not appear to have a significant effect on CC antagonist activity. In contrast, the effect of the alkyl ester substituent was more pronounced where compounds having a Me or Et alkyl ester group showed superior potency (IC(50) in the 10(-7)M range) relative to the reference drug nifedipine (IC(50)=1.40 x 10(-8)M). Replacement of a 2-methyl-3-methoxycarbonylvinyl moiety present in nifedipine by a bioisosteric geminal-dihalocyclopropyl moiety provided a novel class of calcium channel antagonists that do not exhibit any inotropic effect on guinea pig atria.
Mojarrad
Javid S
JS
Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, Alberta, Canada T6G 2N8.
Vo
Dean
D
Velázquez
Carlos
C
Knaus
Edward E
EE
D000818:Animals; D002121:Calcium Channel Blockers / Q000138:chemical synthesis* / Q000494:pharmacology; D002264:Carboxylic Acids / Q000138:chemical synthesis* / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D004952:Esters / Q000737:chemistry; D006168:Guinea Pigs; D006325:Heart Atria; D007082:Ileum; D020128:Inhibitory Concentration 50; D009119:Muscle Contraction / Q000187:drug effects; D009130:Muscle, Smooth / Q000737:chemistry / Q000502:physiology; D013329:Structure-Activity Relationship
D002121:Calcium Channel Blockers; D002264:Carboxylic Acids; D004952:Esters