AT1 receptor ligands: virtual-screening-based design with TOPP descriptors, synthesis, and biological evaluation of pyrrolidine derivatives.
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.
Lamanna
Claudia
C
Dipartimento Farmaco-Chimico, Università degli Studi di Bari, Via E. Orabona 4, 70125 Bari, Italy.
Catalano
Alessia
A
Carocci
Alessia
A
Di Mola
Antonia
A
Franchini
Carlo
C
Tortorella
Vincenzo
V
Vanderheyden
Patrick M L
PM
Sinicropi
Maria S
MS
Watson
Kimberly A
KA
Sciabola
Simone
S
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
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