title: Synthesis, biological activity, and three-dimensional quantitative structure-activity relationship model for a series of benzo[c]quinolizin-3-ones, nonsteroidal inhibitors of human steroid 5alpha-reductase 1.
abstract: New 5alpha-reductase 1 (5alphaR-1) inhibitors were designed to complete a consistent set of analogues suitable for a 3D QSAR study. These compounds were synthesized by a modification of the aza-Robinson annulation, further functionalized by Pd-catalyzed cross-coupling processes, and were tested with human 5alphaR-1 expressed in Chinese hamster ovary 1827 cells. It turned out that the potency of the resulting inhibitors was strongly dependent on the type of substitution at the 8 position, with the IC(50) values ranging from 8.1 to 1050 nM. The construction of this homogeneous set of molecules allowed a 3D QSAR study. In particular, comparative molecular field analysis (CoMFA) was used to correlate the potency of the inhibitors with their physicochemical features. Highly accurate evaluations of the atomic point charges were carried out by means of quantum chemical calculations at the DFT/B3LYP level of theory followed by the RESP fitting procedure. It turned out that increasing the reliability of electrostatic parameters greatly affected the statistical results of the QSAR analysis. The 3D QSAR model proposed could be very useful in the further development of 5alphaR-1 inhibitors, which are suitable candidates to be evaluated as drugs in the treatment of 5alphaR-1 related diseases such as acne and alopecia in men and hirsutism in women.
authors.affiliation: Department of Organic Chemistry U. Schiff, University of Florence, Via della Lastruccia 13, I-50019 Sesto Fiorentino, Italy.
authors.forename: Ernesto G
authors.initials: EG
authors.lastname: Occhiato
authors.forename: Alessandro
authors.initials: A
authors.lastname: Ferrali
authors.forename: Gloria
authors.initials: G
authors.lastname: Menchi
authors.forename: Antonio
authors.initials: A
authors.lastname: Guarna
authors.forename: Giovanna
authors.initials: G
authors.lastname: Danza
authors.forename: Alessandra
authors.initials: A
authors.lastname: Comerci
authors.forename: Rosa
authors.initials: R
authors.lastname: Mancina
authors.forename: Mario
authors.initials: M
authors.lastname: Serio
authors.forename: Gianni
authors.initials: G
authors.lastname: Garotta
authors.forename: Andrea
authors.initials: A
authors.lastname: Cavalli
authors.forename: Marco
authors.initials: M
authors.lastname: De Vivo
authors.forename: Maurizio
authors.initials: M
authors.lastname: Recanatini
mesh_terms: D013741:3-Oxo-5-alpha-Steroid 4-Dehydrogenase / Q000737:chemistry; D058891:5-alpha Reductase Inhibitors; D000818:Animals; D016466:CHO Cells; D006224:Cricetinae; D006801:Humans; D008958:Models, Molecular; D008968:Molecular Conformation; D021281:Quantitative Structure-Activity Relationship; D011807:Quinolizines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology
chemical_list: D058891:5-alpha Reductase Inhibitors; D011807:Quinolizines; D013741:3-Oxo-5-alpha-Steroid 4-Dehydrogenase