title: Identification of a lead pharmacophore for the development of potent nuclear receptor modulators as anticancer and X syndrome disease therapeutic agents.
abstract: A series of tetrahydroisoquinoline-N-phenylamide derivatives were designed, synthesized, and tested for their relative binding affinity and antagonistic activity against androgen receptor (AR). Compound 1b (relative binding affinity, RBA = 6.4) and 1h (RBA = 12.6) showed higher binding affinity than flutamide (RBA = 1), a potent AR antagonist. These two compounds also exerted optimal antagonistic activity against AR in reporter assays. The derivatives were also tested for their activities against another nuclear receptor, farnesoid x receptor (FXR), with most compounds acting as weak antagonists, however, compound 1h behaved as a FXR agonist with activity slightly less than that of chenodeoxycholic acid (CDCA), a natural FXR agonist.
authors.affiliation: Department of Medicinal Chemistry, School of Pharmacy and Institute for Structural Biology and Drug Discovery, Virginia Commonwealth University, Richmond, 23298, USA.
authors.forename: Hsiang-Ru
authors.initials: HR
authors.lastname: Lin
authors.forename: Donald J
authors.initials: DJ
authors.lastname: Abraham
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000494:pharmacology*; D002460:Cell Line; D002626:Chemistry, Pharmaceutical / Q000379:methods*; D002635:Chenodeoxycholic Acid / Q000737:chemistry; D004268:DNA-Binding Proteins / Q000737:chemistry; D015195:Drug Design; D017930:Genes, Reporter; D006801:Humans; D024821:Metabolic Syndrome / Q000188:drug therapy*; D008956:Models, Chemical; D008958:Models, Molecular; D009369:Neoplasms / Q000188:drug therapy*; D011485:Protein Binding; D018160:Receptors, Cytoplasmic and Nuclear / Q000737:chemistry / Q000378:metabolism*; D014157:Transcription Factors / Q000737:chemistry; D015533:Transcriptional Activation; D014162:Transfection; D020798:Two-Hybrid System Techniques; D000099150:Receptor, Farnesoid X-Activated
chemical_list: D000970:Antineoplastic Agents; D002635:Chenodeoxycholic Acid; D004268:DNA-Binding Proteins; D018160:Receptors, Cytoplasmic and Nuclear; D014157:Transcription Factors; D000099150:Receptor, Farnesoid X-Activated