title: A novel type of retinoic acid receptor antagonist: synthesis and structure-activity relationships of heterocyclic ring-containing benzoic acid derivatives.
abstract: 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-1-(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- thiaanthral[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- pyridylmethyl)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.
authors.affiliation: Tsukuba Research Laboratories, Eisai Co., Ltd., Ibaraki, Japan.
authors.forename: H
authors.initials: H
authors.lastname: Yoshimura
authors.forename: M
authors.initials: M
authors.lastname: Nagai
authors.forename: S
authors.initials: S
authors.lastname: Hibi
authors.forename: K
authors.initials: K
authors.lastname: Kikuchi
authors.forename: S
authors.initials: S
authors.lastname: Abe
authors.forename: T
authors.initials: T
authors.lastname: Hida
authors.forename: S
authors.initials: S
authors.lastname: Higashi
authors.forename: I
authors.initials: I
authors.lastname: Hishinuma
authors.forename: T
authors.initials: T
authors.lastname: Yamanaka
mesh_terms: D001565:Benzoates / Q000737:chemistry / Q000494:pharmacology*; D018845:CD11 Antigens / Q000378:metabolism; D002454:Cell Differentiation / Q000187:drug effects; D015195:Drug Design; D006571:Heterocyclic Compounds / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D066298:In Vitro Techniques; D018168:Receptors, Retinoic Acid / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured
chemical_list: D001565:Benzoates; D018845:CD11 Antigens; D006571:Heterocyclic Compounds; D018168:Receptors, Retinoic Acid