4gj5
Crystal structure of renin in complex with NVP-AMQ838 (compound 5)
Structural highlights
DiseaseRENI_HUMAN Defects in REN are a cause of renal tubular dysgenesis (RTD) [MIM:267430. RTD is an autosomal recessive severe disorder of renal tubular development characterized by persistent fetal anuria and perinatal death, probably due to pulmonary hypoplasia from early-onset oligohydramnios (the Potter phenotype).[1] Defects in REN are the cause of familial juvenile hyperuricemic nephropathy type 2 (HNFJ2) [MIM:613092. It is a renal disease characterized by juvenile onset of hyperuricemia, slowly progressive renal failure and anemia.[2] FunctionRENI_HUMAN Renin is a highly specific endopeptidase, whose only known function is to generate angiotensin I from angiotensinogen in the plasma, initiating a cascade of reactions that produce an elevation of blood pressure and increased sodium retention by the kidney. Publication Abstract from PubMedThe small-molecule trans-3,4-disubstituted pyrrolidine 6 was identified from in silico three-dimensional (3D) pharmacophore searches based on known X-ray structures of renin-inhibitor complexes and demonstrated to be a weakly active inhibitor of the human enzyme. The unexpected binding mode of the more potent enantiomer (3S,4S)-6a in an extended conformation spanning the non-prime and S1' pockets of the rh-renin active site was elucidated by X-ray crystallography. Initial structure-activity relationship work focused on modifications of the hydrophobic diphenylamine portion positioned in S1 and extending toward the S2 pocket. Replacement with an optimized P3-P1 pharmacophore interacting to the nonsubstrate S3sp cavity eventually resulted in significantly improved in vitro potency and selectivity. The prototype analogue (3S,4S)-12a of this new class of direct renin inhibitors exerted blood pressure lowering effects in a hypertensive double-transgenic rat model after oral administration. The Discovery of Novel Potent trans-3,4-Disubstituted Pyrrolidine Inhibitors of the Human Aspartic Protease Renin from in silico Three-Dimensional (3D) Pharmacophore Searches.,Lorthiois E, Breitenstein W, Cumin F, Ehrhardt C, Francotte E, Jacoby E, Ostermann N, Sellner H, Kosaka T, Webb R, Rigel D, Hassiepen U, Richert P, Wagner T, Maibaum JK J Med Chem. 2013 Feb 20. PMID:23425156[3] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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