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Merck

Novel selective anti-androgens with a diphenylpentane skeleton.

Bioorganic & medicinal chemistry letters (2010-10-05)
Keisuke Maruyama, Tomomi Noguchi-Yachide, Kazuyuki Sugita, Yuichi Hashimoto, Minoru Ishikawa
ABSTRACT

We have proposed a multi-template approach for drug development, focusing on similar fold structures of proteins, and have effectively generated lead compounds for several drug targets. Modification of these polypharmacological lead compounds is then needed to generate target-selective compounds. In the work presented here, we aimed at separation of the anti-androgen activity and vitamin D activity of previously identified diphenylpentane lead compounds. Based on the determined X-ray crystal structures of androgen receptor and vitamin D receptor, bulky substituents were introduced at the t-butyl group in the lead compounds 2 and 3. As a result of this structural development, we obtained 16c, which exhibits more potent anti-androgen activity (IC(50): 0.13 μM) than clinically used anti-androgen bicalutamide (IC(50): 0.67 μM) with 30-fold selectivity over vitamin D activity. This result indicates that lead compounds obtained via the multi-template approach can indeed be structurally modified to generate target-selective compounds.

MATERIALS
Product Number
Brand
Product Description

Sigma-Aldrich
Pentane, anhydrous, ≥99%
Supelco
Pentane, analytical standard
Sigma-Aldrich
Pentane, ≥99% (GC)
Sigma-Aldrich
Pentane, suitable for HPLC, ≥99.0%
Sigma-Aldrich
Pentane, spectrophotometric grade, ≥99%
Sigma-Aldrich
Pentane, reagent grade, 98%
Sigma-Aldrich
Pentane, puriss. p.a., ≥99.0% (GC)