title: AT1 receptor ligands: virtual-screening-based design with TOPP descriptors, synthesis, and biological evaluation of pyrrolidine derivatives.
abstract: 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.
authors.affiliation: Dipartimento Farmaco-Chimico, Università degli Studi di Bari, Via E. Orabona 4, 70125 Bari, Italy.
authors.forename: Claudia
authors.initials: C
authors.lastname: Lamanna
authors.forename: Alessia
authors.initials: A
authors.lastname: Catalano
authors.forename: Alessia
authors.initials: A
authors.lastname: Carocci
authors.forename: Antonia
authors.initials: A
authors.lastname: Di Mola
authors.forename: Carlo
authors.initials: C
authors.lastname: Franchini
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Tortorella
authors.forename: Patrick M L
authors.initials: PM
authors.lastname: Vanderheyden
authors.forename: Maria S
authors.initials: MS
authors.lastname: Sinicropi
authors.forename: Kimberly A
authors.initials: KA
authors.lastname: Watson
authors.forename: Simone
authors.initials: S
authors.lastname: Sciabola
mesh_terms: D004353:Drug Evaluation, Preclinical; D008024:Ligands; D019808:Losartan / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D011759:Pyrrolidines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D011945:Receptors, Angiotensin / Q000378:metabolism*; D013329:Structure-Activity Relationship
chemical_list: C571002:1-pentanoyl-N-((2'-(1H-tetrazol-5-yl)biphenyl-4-yl)methyl)pyrrolidine-2-carboxamide; D008024:Ligands; D011759:Pyrrolidines; D011945:Receptors, Angiotensin; D019808:Losartan