131906-19-9Relevant academic research and scientific papers
Synthesis and Use of 3-Amino-4-phenyl-2-piperidones and 4-Amino-2-benzazepin-3-ones as Conformationally Restricted Phenylalanine Isosteres in Renin Inhibitors
Laszlo, S. E. de,Bush, B. L.,Doyle, J. J.,Greenlee, W. J.,Hangauer, D. G.,et al.
, p. 833 - 846 (2007/10/02)
The design of P2-P3 conformational restrictions in renin inhibitors by the use of renin computer graphic model led to the synthesis of inhibitors containing N-Boc, N-acetyl, and N-phthalyl derivatives of 3(S)-amino-4(R,S)-2-piperidones and 4(S)-amino-2-benzazepinones in place of phenylalanine in the control compound N-acetyl-L-phenylalanyl-N--1-(S)-(cyclohexylmethyl)-2(S)-hydroxy-5-methylhexyl>-L-norleucinamide (32).The piperidone inhibitors were prepared by utilization of the Evans chiral auxilliary to introduce the amino group with enantioselecivity and also to act as a leaving group in an intramolecular cyclization to the piperidone.The most potent inhibitor, 3(S)-(acetylmino)-α(S)-butyl-N--1(S)-(cyclohexylmethyl)-2(S)-hydroxy-5-methylhexyl>-2-oxo-4(R)-phenyl-1-piperidineacetamide (18, IC50 = 21 nM), was 25-fold less potent than the acyclic control 32.Considerable dependence of potency with the size of the P4 derivative was observed as had been expected based on the presynthetic modeling studies.Attempts to rationalize the observed potencies on the basis of further molecular modeling studies suggested that the loss in inhibitor potency was due to the conformational restrictions distorting the 3S center from the geometry present in the putative extended conformation present when the inhibitor is bound within the renin active site.
β-substituted β-phenylpropionyl chymotrypsins. Structural and stereochemical features in stable acyl enzymes
Reed,Katzenellenbogen
, p. 1162 - 1176 (2007/10/02)
In order to develop effective alternate substrate inhibitors for serine proteases, we have prepared a series of β-substituted β-phenylpropionic acid esters related to some systems known to form stable acyl enzymes with α-chymotrypsin. Some of these compounds were prepared in enantiomerically pure form by asymmetric synthesis. Acyl enzyme species were generated from chymotrypsin by reaction with the active esters, and the progress of deacylation was monitored by the proflavin displacement assay. In some cases, it was possible to distinguish two different deacylation rates that correspond to the two enantiomers. β-Phenylpropionic acyl enzymes with β-substituents that are nonpolar were not especially stable, but a number of the polar derivatives and particularly the acylamino derivatives showed slow rates of deacylation (k(d) less than 0.005 min-1), with three systems showing deacylation enantioselectivities in the range of 500-1500. These results are consistent with a model in which additional stabilization of the acyl enzyme and enantioselectivity in the deacylation process derives from an additional hydrogen bond between the acyl enzyme species (as an acceptor) and the enzyme (as a donor). A number of active site residues that might be involved in this hydrogen bond are discussed.
