4ryc
From Proteopedia
RENIN IN COMPLEXED WITH 4-methoxy-3-(3-methoxypropoxy)-N-{[(3S,4S)-4-{[(4-methylphenyl)sulfonyl]amino}pyrrolidin-3-yl]methyl}-N-(propan-2-yl)benzamide INHIBITOR
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 PubMedRecently, we reported on the discovery of (3S,4S)-disubstituted pyrrolidines (e.g., 2) as inhibitors of the human aspartyl protease renin. In our effort to further expand the scope of this novel class of direct renin inhibitors, a new sub-series was designed in which the prime site substituents are linked to the pyrrolidine core by a (3S)-amino functional group. In particular, analogs bearing the corresponding sulfonamide spacer (50, 51 and 54a) demonstrated a pronounced increase in in vitro potency compared to compound 2. trans-(3S,4S)-Disubstituted pyrrolidines as inhibitors of the human aspartyl protease renin. Part I: Prime site exploration using an amino linker.,Lorthiois E, Cumin F, Ehrhardt C, Kosaka T, Sellner H, Ostermann N, Francotte E, Wagner T, Maibaum J Bioorg Med Chem Lett. 2015 Apr 15;25(8):1782-6. doi: 10.1016/j.bmcl.2015.02.039. , Epub 2015 Feb 21. PMID:25782742[3] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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