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Molecular Pharmacology Fast Forward
First published on November 30, 2007; DOI: 10.1124/mol.107.040089

0026-895X/08/7303-900-908$20.00
Mol Pharmacol 73:900-908, 2008

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Identification of the First Synthetic Steroidogenic Factor 1 Inverse Agonists: Pharmacological Modulation of Steroidogenic Enzymes

Andria L. Del Tredici, Carsten B. Andersen, Erika A. Currier, Steven R. Ohrmund, Luke C. Fairbain, Birgitte W. Lund, Norman Nash, Roger Olsson, and Fabrice Piu

ACADIA Pharmaceuticals Inc, San Diego, California (A.L.D., C.B.A., E.A.C., S.R.O., L.C.F., N.N., F.P.); and ACADIA Pharmaceuticals AB, Malmo, Sweden (B.W.L., R.O.)

Steroidogenic factor SF-1, a constitutively active nuclear hormone receptor, is essential to the development of adrenal and gonadal glands and acts as a shaping factor of sexual determination and differentiation. Its effects are exerted primarily through the control of the synthesis of steroid hormones. The functional cell-based assay Receptor Selection and Amplification Technology (R-SAT) was used to identify potent and selective SF-1 inverse agonists through the screening of a chemical library of drug-like small-molecule entities. Among them, 4-(heptyloxy)phenol (AC-45594), a prototype inverse agonist lead, was used to show that SF-1 constitutive activity can be pharmacologically modulated by a synthetic ligand. In a physiological system of endocrine function, the expression of several reported SF-1 target genes, including SF-1 itself, was inhibited by treatment with AC-45594 and analogs. Thus, pharmacological modulation of SF-1 is critical to its function as an endocrine master regulator and has potentially important consequences to diseases in which SF-1 activity is critical.

Received July 16, 2007; accepted November 28, 2007

Address correspondence to: Dr. Fabrice Piu, ACADIA Pharmaceuticals Inc., 3911 Sorrento Valley Blvd, San Diego, CA 92121. E-mail: fpiu{at}acadia-pharm.com




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