4q1n
From Proteopedia
Structure-based design of 4-hydroxy-3,5-substituted piperidines as direct renin inhibitors
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 PubMedA cis-configured 3,5-disubstituted piperidine direct renin inhibitor, (syn,rac)-1, was discovered as a high-throughput screening hit from a target-family tailored library. Optimization of both the prime and the nonprime site residues flanking the central piperidine transition-state surrogate resulted in analogues with improved potency and pharmacokinetic (PK) properties, culminating in the identification of the 4-hydroxy-3,5-substituted piperidine 31. This compound showed high in vitro potency toward human renin with excellent off-target selectivity, 60% oral bioavailability in rat, and dose-dependent blood pressure lowering effects in the double-transgenic rat model. Structure-based design of substituted piperidines as a new class of highly efficacious oral direct Renin inhibitors.,Ehara T, Irie O, Kosaka T, Kanazawa T, Breitenstein W, Grosche P, Ostermann N, Suzuki M, Kawakami S, Konishi K, Hitomi Y, Toyao A, Gunji H, Cumin F, Schiering N, Wagner T, Rigel DF, Webb RL, Maibaum J, Yokokawa F ACS Med Chem Lett. 2014 Apr 21;5(7):787-92. doi: 10.1021/ml500137b. eCollection, 2014 Jul 10. PMID:25050166[3] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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