title: Synthesis and biological activity of high-affinity retinoic acid receptor antagonists.
abstract: This article reports the synthesis and biological activity of new high affinity retinioic acid receptor (RAR) antagonists. The effect of introducing heteroatoms in the bicyclic ring system of the potent dihydronaphthalene RAR antagonist 8, and the variation of the pendant aromatic group on the ability of these compounds to function as RAR antagonists is discussed. The use of binding, transcriptional, and in vivo assays revealed that the 2,2-dimethylthiochromene analogue 59, and the 2,2-dimethylchromene derivative 85, were the most effective in blocking retinoid agonist induced activity.
authors.affiliation: Department of Chemistry, Allergan Inc., Irvine, CA 92623-9534, USA. johnson_alan@allergan.com
authors.forename: A T
authors.initials: AT
authors.lastname: Johnson
authors.forename: L
authors.initials: L
authors.lastname: Wang
authors.forename: A M
authors.initials: AM
authors.lastname: Standeven
authors.forename: M
authors.initials: M
authors.lastname: Escobar
authors.forename: R A
authors.initials: RA
authors.lastname: Chandraratna
mesh_terms: D000818:Animals; D001565:Benzoates / Q000138:chemical synthesis* / Q000494:pharmacology* / Q000633:toxicity; D006571:Heterocyclic Compounds / Q000737:chemistry / Q000494:pharmacology; D020128:Inhibitory Concentration 50; D009281:Naphthalenes / Q000138:chemical synthesis / Q000494:pharmacology; D018168:Receptors, Retinoic Acid / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism; D047488:Retinoid X Receptors; D012176:Retinoids / Q000633:toxicity; D013329:Structure-Activity Relationship; D013876:Thiophenes / Q000138:chemical synthesis* / Q000494:pharmacology*; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D014158:Transcription, Genetic
chemical_list: C121616:4-((4-(4-ethylphenyl)-2,2-dimethyl-(2H)-thiochromen-6-yl)ethynyl)benzoic acid; D001565:Benzoates; D006571:Heterocyclic Compounds; D009281:Naphthalenes; D018168:Receptors, Retinoic Acid; D011994:Recombinant Proteins; D047488:Retinoid X Receptors; D012176:Retinoids; D013876:Thiophenes; D014157:Transcription Factors; C038864:4-(2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl)-1-propenyl)benzoic acid; C096920:AGN 193109