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 prepared, and the binding affinity and antagonism of its members against all-trans-retinoic acid were evaluated by in vitro assay systems using human promyelocytic leukemia (HL-60) cells. Structure-activity relationships indicated that both an N-substituted pyrrole or pyrazole (1-position) 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 acid (31), 4-[4,5,7,8,9,10-hexahydro-7,7, 10,10-tetramethyl-1-(3-pyridylmethyl)-5- thiaanthra[1,2-b] pyrrol-3-yl]benzoic acid (40), and 4-[4,5,7,8,9,10-hexahydro-7,7,10,10-tetramethyl-1-(3-pyridylemethyl)anthra[2,1-d]pyrazol-3-yl}]benzoic acid (55), all of which possess a 3-pyridylmethyl group at the five-membered ring nitrogen atom.