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AT 1 Receptor Ligands: Virtual‐Screening‐Based Design with TOPP Descriptors, Synthesis, and Biological Evaluation of Pyrrolidine Derivatives
Author(s) -
Lamanna Claudia,
Catalano Alessia,
Carocci Alessia,
Di Mola Antonia,
Franchini Carlo,
Tortorella Vincenzo,
Vanderheyden Patrick M. L.,
Sinicropi Maria S.,
Watson Kimberly A.,
Sciabola Simone
Publication year - 2007
Publication title -
chemmedchem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.817
H-Index - 100
eISSN - 1860-7187
pISSN - 1860-7179
DOI - 10.1002/cmdc.200700082
Subject(s) - pyrrolidine , chemistry , quantitative structure–activity relationship , virtual screening , stereochemistry , biological activity , combinatorial chemistry , computational biology , biology , in vitro , biochemistry , pharmacophore
As a continuing effort to establish the structure–activity relationships (SARs) within the series of the angiotensin II antagonists (sartans), a pharmacophoric model was built by using novel TOPP 3D descriptors. Statistical values were satisfactory (PC4: r 2 =0.96, q 2 (5 random groups) =0.84; SDEP=0.26) and encouraged the synthesis and consequent biological evaluation of a series of new pyrrolidine derivatives. SAR together with a combined 3D quantitative SAR and high‐throughput virtual screening showed that the newly synthesized 1‐acyl‐ N ‐(biphenyl‐4‐ylmethyl)pyrrolidine‐2‐carboxamides may represent an interesting starting point for the design of new antihypertensive agents. In particular, biological tests performed on CHO‐hAT 1 cells stably expressing the human AT 1 receptor showed that the length of the acyl chain is crucial for the receptor interaction and that the valeric chain is the optimal one.