3q3t | pdb_00003q3t
Alkyl Amine Renin Inhibitors: Filling S1 from S3
Structural highlights
Disease[RENI_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] Function[RENI_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 PubMedStructure-based design led to the discovery of a novel class of renin inhibitors in which an unprecedented phenyl ring filling the S1 site is attached to the phenyl ring filling the S3 pocket. Optimization for several parameters including potency in the presence of human plasma, selectivity against CYP3A4 inhibition and improved rat oral bioavailability led to the identification of 8d which demonstrated antihypertensive efficacy in a transgenic rat model of human hypertension. Biphenyl/diphenyl ether renin inhibitors: Filling the S1 pocket of renin via the S3 pocket.,Yuan J, Simpson RD, Zhao W, Tice CM, Xu Z, Cacatian S, Jia L, Flaherty PT, Guo J, Ishchenko A, Wu Z, McKeever BM, Scott BB, Bukhtiyarov Y, Berbaum J, Panemangalore R, Bentley R, Doe CP, Harrison RK, McGeehan GM, Singh SB, Dillard LW, Baldwin JJ, Claremon DA Bioorg Med Chem Lett. 2011 Aug 15;21(16):4836-43. Epub 2011 Jun 17. PMID:21741239[3] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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