Effect of structural modifications in the C7-C11 region of the retinoid skeleton on biological activity in a series of aromatic retinoids

• Published in: Journal of medicinal chemistry 1989-07, Vol.32 (7), p.1504-1517
• Main Authors: Dawson, Marcia I, Hobbs, Peter D, Derdzinski, Krzysztof A, Chao, Wan Ru, Frenking, Gernot, Loew, Gilda H, Jetten, Anton M, Napoli, Joseph L, Williams, John B
• Format: Article
• Language: English
• Subjects: Animals; Cells, Cultured; Chemical Phenomena; Chemistry; Chick Embryo; Condensed benzenic and aromatic compounds; Exact sciences and technology; Male; Molecular Conformation; Organic chemistry; Preparations and properties; Rabbits; Retinoids - chemical synthesis; Retinoids - pharmacology; Spectrophotometry, Ultraviolet; Structure-Activity Relationship
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm00127a018

A series of conformationally restricted analogues of (E)-4-[2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl)propenyl ] benzoic acid--(E)-4-[1-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl)-2 - propenyl]benzoic acid, (E)-4-[3-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl)-2-bu ten- 2-yl]benzoic acid, trans-4-[2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl) cyclopropyl]benzoic acid, 4-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-anthracenyl)benzoic acid, 6-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl)-2- naphthalenecarboxylic acid, 6-(5,6,7,8-tetrahydro-3,5,5,8,8-pentamethyl-2-naphthalenyl)-2- naphthalenecarboxylic acid and 6-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl)-5-methyl-2- naphthalenecarboxylic acid--were synthesized and screened for retinoid biological activity. Comparison of the conformers of these analogues generated by molecular mechanics calculations with the biological activity profiles of these compounds indicates that geometric constraints required for high biological activity are imposed on the bridge joining the two aromatic ring systems by the retinoid receptor.