A NOVEL TYPE OF RETINOIC ACID RECEPTOR ANTAGONIST - SYNTHESIS AND STRUCTURE-ACTIVITY-RELATIONSHIPS OF HETEROCYCLIC RING-CONTAINING BENZOIC-ACID DERIVATIVES

A new series of heterocyclic ring-containing benzoic acids was prepare d, and the binding affinity and antagonism of its members against all- trans-retinoic acid were evaluated by in vitro assay systems using hum an promyelocytic leukemia (HL-60) cells. Structure-activity relationsh ips indicated that both an N-substituted pyrrole or pyrazole (1-positi on) and a hydrophobic region, with these linked by a ring system, were indispensable for effective antagonism. Among the compounds evaluated , optimal antagonism was exhibited by 4-[4,5,7,8,9,10-hexahydro-7,7,10 ,10-tetramethyl-l- (3-pyridylmethyl)anthra[1,2-b]pyrrol-3-yl]benzoic a cid (31), 4-[4,5,7,8,9,10-hexahydro-7,7, 10,10-tetramethyl-1-(3-pyridy lmethyl)-5- thiaanthra[1,2-b] pyrrol-3-yl]benzoic acid (40), and -pyri dylemethyl)anthra[2,1-d]pyrazol-3-yl}]benzoic acid (55), all of which possess a 3-pyridylmethyl group at the five-membered ring nitrogen ato m.