Enantioselective nonsteroidal aromatase inhibitors identified through a multidisciplinary medicinal chemistry approach.
To identify enantioselective nonsteroidal aromatase inhibitors, a multidisciplinary medicinal chemistry approach was pursued. First, our earlier CoMFA model [Bioorg. Med. Chem. 1998,6, 377-388] was extended taking purposely into account previously discovered enantioselective aromatase inhibitors. The 3D QSAR model was then exploited to design chiral ligands, whose configurational assignment was obtained, after HPLC separation, by means of a combination of circular dichroism measurements and time dependent density functional calculations. Finally, the new enantiomeric inhibitors were separately tested to ascertain both their potency against the cytochrome P450 aromatase (CYP19; EC 1.14.14.1), and their selectivity relative to another enzyme of the P450 family. A satisfactory agreement between experimental and predicted data allowed us to assert that a properly built "enantioselective CoMFA model" might constitute a useful tool for addressing enantioselective ligands design.
Cavalli
Andrea
A
Department of Pharmaceutical Sciences, University of Bologna, Via Belmeloro, 6, I-40126 Bologna, Italy.
Bisi
Alessandra
A
Bertucci
Carlo
C
Rosini
Carlo
C
Paluszcak
Anja
A
Gobbi
Silvia
S
Giorgio
Egidio
E
Rampa
Angela
A
Belluti
Federica
F
Piazzi
Lorna
L
Valenti
Piero
P
Hartmann
Rolf W
RW
Recanatini
Maurizio
M
D001141:Aromatase / Q000737:chemistry*; D047072:Aromatase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry; D001578:Benzopyrans / Q000138:chemical synthesis* / Q000737:chemistry; D002942:Circular Dichroism; D015195:Drug Design; D006801:Humans; D008024:Ligands; D008861:Microsomes / Q000201:enzymology; D008958:Models, Molecular; D008968:Molecular Conformation; D010920:Placenta / Q000201:enzymology; D021281:Quantitative Structure-Activity Relationship; D013056:Spectrophotometry, Ultraviolet; D013237:Stereoisomerism; D013254:Steroid 17-alpha-Hydroxylase / Q000037:antagonists & inhibitors / Q000737:chemistry
D047072:Aromatase Inhibitors; D001578:Benzopyrans; D008024:Ligands; D001141:Aromatase; D013254:Steroid 17-alpha-Hydroxylase