Novel heterocyclic analogues of the new potent class of calcium entry blockers: 1-[[4-(aminoalkoxy)phenyl]sulfonyl]indolizines.
Several heterocyclic analogues of the potent 1-[[4-(aminoalkoxy)phenyl]sulfonyl]indolizines were synthesized and evaluated for their antagonistic calcium activities in comparison with the 1-sulfonylindolizine SR 33557 and the usual calcium antagonist references verapamil, cis-(+)-diltiazem, and nifedipine. The bicyclic nine-membered rings were, in general, more potent than the bicyclic 10-membered or five-membered rings. Among the bicyclic nine-membered rings, the indole nucleus appeared to be extremely favorable to support the calcium antagonistic activity. In particular, compound 36, with an IC50 value for the inhibition of [3H]nitrendipine equal to 0.072 nM, is among the most potent calcium antagonist known. This compound has been selected for clinical development.
Gubin
J
J
Sanofi Research Center, Brussels, Belgium.
de Vogelaer
H
H
Inion
H
H
Houben
C
C
Lucchetti
J
J
Mahaux
J
J
Rosseels
G
G
Peiren
M
M
Clinet
M
M
Polster
P
P
D000818:Animals; D002121:Calcium Channel Blockers / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D002540:Cerebral Cortex / Q000187:drug effects / Q000378:metabolism; D006168:Guinea Pigs; D006571:Heterocyclic Compounds / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D007212:Indolizines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D008297:Male; D009131:Muscle, Smooth, Vascular / Q000187:drug effects; D010627:Phenethylamines / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D013329:Structure-Activity Relationship
D002121:Calcium Channel Blockers; D006571:Heterocyclic Compounds; D007212:Indolizines; D010627:Phenethylamines; C059901:fantofarone