Novel selective anti-androgens with a diphenylpentane skeleton.
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.
Maruyama
Keisuke
K
Institute of Molecular & Cellular Biosciences, The University of Tokyo, 1-1-1 Yayoi, Bunkyo-ku, Tokyo 113-0032, Japan.
Noguchi-Yachide
Tomomi
T
Sugita
Kazuyuki
K
Hashimoto
Yuichi
Y
Ishikawa
Minoru
M
D000726:Androgen Antagonists / Q000737:chemistry / Q000494:pharmacology*; D018360:Crystallography, X-Ray; D020128:Inhibitory Concentration 50; D008958:Models, Molecular; D010420:Pentanes / Q000737:chemistry*; D011487:Protein Conformation; D011944:Receptors, Androgen / Q000737:chemistry / Q000187:drug effects; D018167:Receptors, Calcitriol / Q000737:chemistry / Q000187:drug effects
D000726:Androgen Antagonists; D010420:Pentanes; D011944:Receptors, Androgen; D018167:Receptors, Calcitriol; C033353:pentane