title: Synthesis and biological evaluation of 3-tetrazolo steroidal analogs: Novel class of 5α-reductase inhibitors.
abstract: In the present study, a series of steroidal tetrazole derivatives of androstane and pregnane have been prepared in which the tetrazole moiety was appended at C-3 and 17a-aza locations. 3-Tetrazolo-3,5-androstadien-17-one (6), 3-tetrazolo-19-nor-3,5-androstadien-17-one (10), 3-tetrazolo-3,5-pregnadien-20-one (14), 17a-substituted 3-tetrazolo-17a-aza-D-homo-3,5-androstadien-17-one (26-31) and 3-(2-acetyltetrazolo)-17a-aza-d-homo-3,5-androstadien-17-one (32) were synthesized from dehydroepiandrosterone acetate (1) through multiple synthetic steps. Some of the synthesized compounds were evaluated for their in vitro 5α-reductase (5AR) inhibitory activity by measuring the conversion of [(3)H] androstenedione in human embryonic kidney (HEK) cells. In vivo 5α-reductase inhibitory activity also showed a significant reduction (p <0.05) in rat prostate weight. The most potent compound 14 showed 5AR-2 inhibition with IC50 being 15.6nM as compared to clinically used drug finasteride (40nM). There was also a significant inhibition of 5AR-1 with IC50 547nM compared to finasteride (453nM).
authors.affiliation: University Institute of Pharmaceutical Sciences, Panjab University, Chandigarh 160014, India.
authors.forename: Saurabh
authors.initials: S
authors.lastname: Aggarwal
authors.affiliation: University Institute of Pharmaceutical Sciences, Panjab University, Chandigarh 160014, India.
authors.forename: Manoj Kumar
authors.initials: MK
authors.lastname: Mahapatra
authors.affiliation: University Institute of Pharmaceutical Sciences, Panjab University, Chandigarh 160014, India.
authors.forename: Rajnish
authors.initials: R
authors.lastname: Kumar
authors.affiliation: University Institute of Pharmaceutical Sciences, Panjab University, Chandigarh 160014, India; School of Pharmacy & Emerging Sciences, Baddi University of Emerging Sciences & Technology, Baddi, Himachal Pradesh, India.
authors.forename: Tilak R
authors.initials: TR
authors.lastname: Bhardwaj
authors.affiliation: Helmholtz Institute for Pharmaceutical Research Saarland (HIPS), Campus 81, D-66123 Saarbrücken, Germany; Department of Pharmacy, Pharmaceutical and Medicinal Chemistry, Saarland University, Campus C23, Saarbrücken, Germany.
authors.forename: Rolf W
authors.initials: RW
authors.lastname: Hartmann
authors.affiliation: Helmholtz Institute for Pharmaceutical Research Saarland (HIPS), Campus 81, D-66123 Saarbrücken, Germany.
authors.forename: Jörg
authors.initials: J
authors.lastname: Haupenthal
authors.affiliation: University Institute of Pharmaceutical Sciences, Panjab University, Chandigarh 160014, India. Electronic address: manoj_uips@pu.ac.in.
authors.forename: Manoj
authors.initials: M
authors.lastname: Kumar
mesh_terms: D058891:5-alpha Reductase Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology; D000731:Androstanes / Q000138:chemical synthesis* / Q000494:pharmacology; D000735:Androstenedione / Q000378:metabolism; D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D045744:Cell Line, Tumor; D042944:Cholestenone 5 alpha-Reductase / Q000378:metabolism; D004822:Epididymis / Q000187:drug effects / Q000201:enzymology; D018120:Finasteride / Q000494:pharmacology; D015870:Gene Expression; D057809:HEK293 Cells; D006801:Humans; D007527:Isoenzymes / Q000037:antagonists & inhibitors / Q000378:metabolism; D008297:Male; D010957:Plasmids / Q000737:chemistry / Q000378:metabolism; D011278:Pregnanes / Q000138:chemical synthesis* / Q000494:pharmacology; D011467:Prostate / Q000187:drug effects* / Q000201:enzymology; D051381:Rats; D012669:Seminal Vesicles / Q000187:drug effects / Q000201:enzymology; D013329:Structure-Activity Relationship; D013777:Tetrazoles / Q000138:chemical synthesis* / Q000494:pharmacology; D014162:Transfection
chemical_list: D058891:5-alpha Reductase Inhibitors; D000731:Androstanes; D000970:Antineoplastic Agents; D007527:Isoenzymes; D011278:Pregnanes; D013777:Tetrazoles; D000735:Androstenedione; D018120:Finasteride; D042944:Cholestenone 5 alpha-Reductase
keywords: 5AR; Finasteride; HEK; Testosterone; Tetrazole