New CYP17 Hydroxylase Inhibitors: Synthesis, Biological Evaluation, QSAR, and Molecular Docking Study of New Pregnenolone Analogs. Issue 12 (24th September 2014)

• Record Type: Journal Article
• Authors: Al‐Masoudi, Najim A.; Ali, Dawood S.; Saeed, Bahjat; Hartmann, Rolf W.; Engel, Matthias; Rashid, Sajid; Saeed, Aamer
• Is Part Of: Archiv der Pharmazie. Volume 347:Issue 12(2014:Dec.)
• Page Start: 896
• Page End: 907
• Publication Date: 2014-09-24
• Subjects: Pharmaceutical chemistry -- Periodicals; Pharmacology -- Periodicals; 615.19
• DOI: 10.1002/ardp.201400255
• Languages: English
• ISSNs: 0365-6233

Abstract

<abstract abstract-type="main"> <title> <x xml:space="preserve">Abstract</x> </title> <sec id="ardp201400255-sec-0001" sec-type="section"> <p>A new series of pregnenonlone analogs were synthesized and evaluated for their inhibitory activity against cytochrome P450 (CYP17 hydroxylase enzyme). In general, the 5‐aryl‐1, 3, 4‐thiadiazol‐2‐yl)‐imino‐pregnenolone derivatives <bold>11</bold>–<bold>15</bold> were more active than the sulfonate <bold>24</bold>–<bold>31</bold> and the ester <bold>37</bold>–<bold>41</bold> analogs. Derivative <bold>12</bold> showed optimal activity in this series, with IC₅₀ values of 2.5 µM compared with the standard abiraterone (IC₅₀ = 0.07 µM). However, the analogs <bold>11</bold> and <bold>25</bold> showed a better selectivity profile (81.5 and 82.7% inhibition of hydroxylase, respectively), which may be a useful lead in CYP17 inhibition studies. Molecular docking studies demonstrated quite similar binding patterns of all new pregnenolone derivatives at the active site of CYP17 through hydrogen bonding and hydrophobic interaction.</p> </sec> </abstract>