Renin inhibitors containing a pyridyl amino diol derived C-terminus

Abstract

Based on the concept of transition-state analogs, a series of nonpeptide renin inhibitors with the new (2S,3R,4S)-2-amino-1-cyclohexyl-3,4-dihydroxy-6-(2-pyridyl)hexane moiety at the C-terminal functionality were synthesized and evaluated for inhibition of renin both in vitro and in vivo. All compounds exhibited potencies in the nanomolar or even subnanomolar range when tested versus human renin in vitro. Selected inhibitors were evaluated in anesthetized, sodium-depleted rhesus monkeys and produced a marked reduction in mean arterial blood pressure (MAP) upon intraduodenal administration of a dose of 2 mg/kg. Compound 38 (S 2864) containing an amino piperidyl succinic acid derived N-terminal is the most promising member in this series. 38 inhibited human renin with an IC50 of 0.38 nM, did not affect other human aspartic proteinases, and decreased mean arterial blood pressure significantly by 27% with a duration of action of 90 min after administration of 2 mg/kg id in anesthetized, sodium-depleted rhesus monkeys.

Decades-old renin inhibitors are still struggling to find a niche in antihypertensive therapy. A fleeting look at the old and the promising new molecules

“…One such potent compound was N-terminal derived piperidyl succinic acid that inhibited the human renin activity at an IC 50 of 0.38 nM. 33 Since the 1990′s, High through put screening (HTS) has emerged as a discovery tool and many millions of compounds have been produced and assessed for an activity at the target protein. But it had low success rates in the identification of potential hit molecules.…”

Ordered Mesoporous Silica as Supports in the Heterogeneous Asymmetric Catalysis

“…Hydrogenation products like chiral 2-substituted succinic acids have attracted a great interest for their utility as chiral building blocks in recent years [63,64]. Holderich et al Cabosil (convex).…”

Asymmetric Synthesis of Functionalized Bicyclic β‐Amino Alcohols by Cascade Hydrometallation–Cyclization–Reduction of Glycinyl‐Substituted Alkenylsulfox­imines – Application to the Synthesis of an Aggrecanase Inhibitor Mimic

“…The asymmetric synthesis of succinic acid 48 was carried out by the oxazolidinone method, [34] which has already been successfully applied to the synthesis of structurally related acids. [35,36] Coupling of acid 51 with chiral auxiliary 52 gave oxazolidinone 53 in 82 % yield. The successive treatment of 53 with sodium hexamethyldisilazide and tert-butylbromoacetate afforded substituted amide 54 with Ն 98 % de (NMR) in 71 % yield.…”

“…Amide 54 was assigned as the R-configuration on the basis of literature precedent. [34][35][36] Hydrolysis of amide 54 with LiOH/H 2 O 2 furnished the R-configured succinic acid 48 in 97 % yield. The crucial coupling of the two building blocks, the enantio-and diastereopure amine 47 containing 0.5 equiv.…”