A novel class of calcium-entry blockers: the 1[[4-(aminoalkoxy)phenyl]sulfonyl]indolizines.
The synthesis and initial biological evaluation of a series of 1-sulfonylindolizines is described. These compounds have been shown to be representatives of a novel class of potent, slow-channel calcium antagonists. All compounds were found to be at least as active as the reference calcium antagonists verapamil and cis-(+)-diltiazem. Structure-activity relationship studies have shown that all compounds possessing an aralkyl group in the amine moiety and an isopropyl or cyclopropyl group at the 2 position of the indolizine are among the most potent calcium antagonists known outside the 1,4-dihydropyridine series. The IC50 values for the inhibition of [3H]nitrendipine binding vary between 0.19 and 4.5 nM whereas the IC50 value for nifedipine is 2.5 nM. One of the compounds in this group (9ab) has now been selected for clinical development.
Gubin
J
J
Sanofi Research Center, Brussels, Belgium.
Lucchetti
J
J
Mahaux
J
J
Nisato
D
D
Rosseels
G
G
Clinet
M
M
Polster
P
P
Chatelain
P
P
D000818:Animals; D001665:Binding Sites / Q000187:drug effects; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D002121:Calcium Channel Blockers / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D006168:Guinea Pigs; D007212:Indolizines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D008297:Male; D010627:Phenethylamines / Q000138:chemical synthesis* / Q000494:pharmacology; D051381:Rats; D011919:Rats, Inbred Strains; D013329:Structure-Activity Relationship
D002121:Calcium Channel Blockers; D007212:Indolizines; D010627:Phenethylamines; C059901:fantofarone