Design, Synthesis, and 3D QSAR of Novel Potent and Selective Aromatase Inhibitors

• Published in: Journal of medicinal chemistry 2004-12, Vol.47 (27), p.6792-6803
• Main Authors: Leonetti, Francesco, Favia, Angelo, Rao, Angela, Aliano, Rosaria, Paluszcak, Anja, Hartmann, Rolf W, Carotti, Angelo
• Format: Article
• Language: English
• Subjects: Antineoplastic agents; Antineoplastic Agents - chemical synthesis; Antineoplastic Agents - chemistry; Aromatase - chemistry; Aromatase Inhibitors - chemical synthesis; Aromatase Inhibitors - chemistry; Biological and medical sciences; Drug Design; General aspects; Humans; Medical sciences; Pharmacology. Drug treatments; Quantitative Structure-Activity Relationship; Static Electricity; Steroid 17-alpha-Hydroxylase - antagonists & inhibitors
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm049535j

The design, synthesis, and biological evaluation of a series of new aromatase inhibitors bearing an imidazole or triazole ring linked to a fluorene (A), indenodiazine (B), or coumarin scaffold (C) are reported. Properly substituted coumarin derivatives displayed the highest aromatase inhibitory potency and selectivity over 17-alpha-hydroxylase/17−20 lyase. The modeling of the aromatase inhibition data by Comparative Molecular Field Analysis (CoMFA/GOLPE 3D QSAR approach) led to the development of a PLS model with good fitting and predictive powers (n = 22, ONC = 3, r 2 = 0.949, s = 0.216, and q 2 = 0.715). The relationship between aromatase inhibition and the steric and electrostatic fields generated by the examined azole inhibitors enables a clear understanding of the nature and spatial location of the main interactions modulating the aromatase inhibitory potency.