title: Activity landscape analysis of novel 5α-reductase inhibitors.
abstract: Inhibitors of the enzyme 5[Formula: see text]-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.
authors.affiliation: Departamento de Farmacia, Facultad de Química, Universidad Nacional Autónoma de México, Avenida Universidad 3000, 04510, Mexico, DF, Mexico.|Facultad de Medicina, PECEM, Universidad Nacional Autónoma de México, Avenida Universidad 3000, 04510, Mexico, DF, Mexico.
authors.forename: J Jesús
authors.initials: JJ
authors.lastname: Naveja
authors.affiliation: Departamento de Farmacia, Facultad de Química, Universidad Nacional Autónoma de México, Avenida Universidad 3000, 04510, Mexico, DF, Mexico.
authors.forename: Francisco
authors.initials: F
authors.lastname: Cortés-Benítez
authors.affiliation: Departamento de Farmacia, Facultad de Química, Universidad Nacional Autónoma de México, Avenida Universidad 3000, 04510, Mexico, DF, Mexico.
authors.forename: Eugene
authors.initials: E
authors.lastname: Bratoeff
authors.affiliation: Departamento de Farmacia, Facultad de Química, Universidad Nacional Autónoma de México, Avenida Universidad 3000, 04510, Mexico, DF, Mexico. jose.medina.franco@gmail.com.
authors.forename: José L
authors.initials: JL
authors.lastname: Medina-Franco
mesh_terms: D058891:5-alpha Reductase Inhibitors / Q000737:chemistry* / Q000494:pharmacology; D000736:Androstenes / Q000737:chemistry* / Q000494:pharmacology; D062126:Databases, Chemical; D006801:Humans; D008297:Male; D015394:Molecular Structure; D011278:Pregnanes / Q000737:chemistry* / Q000494:pharmacology; D011470:Prostatic Hyperplasia / Q000188:drug therapy / Q000201:enzymology; D011471:Prostatic Neoplasms / Q000188:drug therapy / Q000201:enzymology; D013329:Structure-Activity Relationship
chemical_list: D058891:5-alpha Reductase Inhibitors; D000736:Androstenes; D011278:Pregnanes
keywords: Activity cliff generators; Benign prostatic hyperplasia; Chemical space; Chemoinformatics; Prostatic 5-reductase; Structure–activity relationships
references.citation: Expert Opin Drug Discov. 2012 Jun;7(6):463-73
references.pmid: 22475223
references.citation: Chem Pharm Bull (Tokyo). 2005 Dec;53(12):1515-8
references.pmid: 16327180
references.citation: J Chem Inf Model. 2008 Mar;48(3):646-58
references.pmid: 18303878
references.citation: J Steroid Biochem Mol Biol. 2007 Oct;107(1-2):48-56
references.pmid: 17629476
references.citation: J Steroid Biochem Mol Biol. 2013 Sep;137:199-222
references.pmid: 23688836
references.citation: J Chem Inf Model. 2005 Jan-Feb;45(1):177-82
references.pmid: 15667143
references.citation: J Biomol Screen. 2011 Sep;16(8):862-8
references.pmid: 21821786
references.citation: J Steroid Biochem Mol Biol. 2008 Sep;111(3-5):232-9
references.pmid: 18625316
references.citation: Mol Divers. 2014 Aug;18(3):599-610
references.pmid: 24710715
references.citation: Steroids. 2009 Oct;74(10-11):793-802
references.pmid: 19406144
references.citation: J Med Chem. 2014 Jan 9;57(1):18-28
references.pmid: 23981118
references.citation: Steroids. 2011 Nov;76(12):1241-6
references.pmid: 21729714
references.citation: Drug Discov Today. 2013 Aug;18(15-16):732-9
references.pmid: 23583765
references.citation: Differentiation. 2011 Nov-Dec;82(4-5):200-10
references.pmid: 21664759
references.citation: Chem Pharm Bull (Tokyo). 2001 Sep;49(9):1081-4
references.pmid: 11558590
references.citation: J Chem Inf Model. 2006 Jul-Aug;46(4):1535
references.pmid: 16859285
references.citation: J Med Chem. 2012 Apr 12;55(7):2932-42
references.pmid: 22236250
references.citation: Chem Pharm Bull (Tokyo). 2003 Oct;51(10):1132-6
references.pmid: 14519916
references.citation: Endocrinology. 1984 Jun;114(6):2100-6
references.pmid: 6539197
references.citation: Chem Biol Drug Des. 2007 Nov;70(5):393-412
references.pmid: 17927720
references.citation: Steroids. 2010 Jul;75(7):499-505
references.pmid: 20359488
references.citation: Eur J Med Chem. 2010 Feb;45(2):476-81
references.pmid: 19906465
references.citation: J Enzyme Inhib Med Chem. 2009 Jun;24(3):655-62
references.pmid: 18825535
references.citation: Int J Mol Sci. 2010 Oct 08;11(10):3846-66
references.pmid: 21152304
references.citation: Chem Pharm Bull (Tokyo). 2004 May;52(5):535-9
references.pmid: 15133203
references.citation: J Enzyme Inhib Med Chem. 2006 Aug;21(4):371-8
references.pmid: 17059168
references.citation: Expert Opin Drug Discov. 2015 Oct;10(10):1059-70
references.pmid: 26289576
references.citation: Am J Med Sci. 1995 Jun;309(6):322-5
references.pmid: 7539584
references.citation: J Med Chem. 1999 Feb 25;42(4):573-83
references.pmid: 10052964
references.citation: Steroids. 2005 Mar;70(3):217-24
references.pmid: 15763601
references.citation: J Chem Inf Model. 2012 Oct 22;52(10):2485-93
references.pmid: 22989212
references.citation: Bioorg Med Chem. 2010 Nov 1;18(21):7380-91
references.pmid: 20888242
references.citation: J Steroid Biochem Mol Biol. 2011 Nov;127(3-5):367-73
references.pmid: 21782943
references.citation: Steroids. 2010 Feb;75(2):109-53
references.pmid: 19879888
references.citation: J Biomol Screen. 2005 Oct;10(7):682-6
references.pmid: 16170046
references.citation: J Chem Inf Model. 2010 May 24;50(5):742-54
references.pmid: 20426451
references.citation: N Engl J Med. 2003 Jul 17;349(3):215-24
references.pmid: 12824459
references.citation: Steroids. 2010 Jun;75(6):411-8
references.pmid: 20170668
references.citation: J Steroid Biochem Mol Biol. 2008 Sep;111(3-5):275-81
references.pmid: 18644453
references.citation: Chem Rev. 2005 Sep;105(9):3352-70
references.pmid: 16159155
references.citation: Future Med Chem. 2015;7(9):1197-211
references.pmid: 26132526