Activity landscape analysis of novel 5α-reductase inhibitors

• Published in: Molecular diversity 2016-08, Vol.20 (3), p.771-780
• Main Authors: Naveja, J. Jesús, Cortés-Benítez, Francisco, Bratoeff, Eugene, Medina-Franco, José L.
• Format: Article
• Language: English
• Subjects: 5-alpha Reductase Inhibitors - chemistry; 5-alpha Reductase Inhibitors - pharmacology; Androstenes - chemistry; Androstenes - pharmacology; Biochemistry; Biomedical and Life Sciences; Databases, Chemical; Humans; Life Sciences; Male; Molecular Structure; Organic Chemistry; Pharmacy; Polymer Sciences; Pregnanes - chemistry; Pregnanes - pharmacology; Prostatic Hyperplasia - drug therapy; Prostatic Hyperplasia - enzymology; Prostatic Neoplasms - drug therapy; Prostatic Neoplasms - enzymology; Short Communication; Structure-Activity Relationship
• ISSN: 1381-1991; 1573-501X
• DOI: 10.1007/s11030-016-9659-x

Inhibitors of the enzyme 5 α -reductase (5aR) are promising therapeutic agents for the treatment of benign prostatic hyperplasia (BPH) and prostate cancer. The lack of structural data of the enzyme 5aR prompts the application of ligand-based approaches to systematically explore the activity landscape of 5aR inhibitors. As part of an effort to develop inhibitors of this enzyme for the treatment of BPH, herein we discuss a chemoinformatic-based analysis of the activity landscape of a novel set of 53 novel pregnane and androstene compounds. It was found that, in general, for each pair of compounds in the set, as the structure similarity of the compounds increases the corresponding potency difference decreases. These results are in agreement with an overall smooth activity landscape. However, two potent activity cliff generators were identified pointing to specific small structural changes that have a large impact on the inhibition of 5aR.