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J Med Chem. 2012 Oct 11;55(19):8464-76. doi: 10.1021/jm300930n. Epub 2012 Sep 24.

Novel aromatase inhibitors by structure-guided design.

Author information

1
Department of Pharmacology, State University of New York Upstate Medical University, Syracuse, NY 13210, USA. ghoshd@upstate.edu

Abstract

Human cytochrome P450 aromatase catalyzes with high specificity the synthesis of estrogens from androgens. Aromatase inhibitors (AIs) such as exemestane, 6-methylideneandrosta-1,4-diene-3,17-dione, are preeminent drugs for the treatment of estrogen-dependent breast cancer. The crystal structure of human placental aromatase has shown an androgen-specific active site. By utilization of the structural data, novel C6-substituted androsta-1,4-diene-3,17-dione inhibitors have been designed. Several of the C6-substituted 2-alkynyloxy compounds inhibit purified placental aromatase with IC(50) values in the nanomolar range. Antiproliferation studies in a MCF-7 breast cancer cell line demonstrate that some of these compounds have EC(50) values better than 1 nM, exceeding that for exemestane. X-ray structures of aromatase complexes of two potent compounds reveal that, per their design, the novel side groups protrude into the opening to the access channel unoccupied in the enzyme-substrate/exemestane complexes. The observed structure-activity relationship is borne out by the X-ray data. Structure-guided design permits utilization of the aromatase-specific interactions for the development of next generation AIs.

PMID:
22951074
PMCID:
PMC3469775
DOI:
10.1021/jm300930n
[Indexed for MEDLINE]
Free PMC Article

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