Design and synthesis of thrombin inhibitors

Abstract

As part of our programme directed at the development of enzyme inhibitors based on transition-state mimics, we discovered in the early 1980s that P3-PY fragments of human fibrinogen As, containing the ketomethylene isostere Arg-w[COCH2]GIy at P1-PI', were potent inhibitors of thrombin. Such low-molecular-weight inhibitors are expected to be clinically useful as anticoagulant drugs. In our more recent investigations, the P1-PI' moiety has been replaced with various arginine or lysine ketohes. The resulting compounds showed the following order of thrombin inhibitory potency: ec-ketoesters > fluoroketones > alkoxymethylketones > difluoro-13-ketoamides > [3-ketoesters > alkyl ketones. In contrast to all other lysine/arginine pairs studied previously, the inhibitor based on a lysine ~-ketoester proved superior to the corresponding arginine analogue. A possible explanation for this finding is discussed. All the highly electrophilic ketones (e.g., fluoroketones) were found to exhibit slow-binding kinetics with thrombin, which is likely to be a disadvantage in clinical use. Alkoxymethyl ketones were devoid of such behaviour and have been developed further to yield nanomolar inhibitors of low molecular weight and good selectivity for thrombin. One of these ketones was found to compare favourably with known thrombin inhibitors in anticoagulant assays. The synthesis of various types of inhibitor mentioned above is described, together with structure-activity correlations for inhibition of thrombin.

Difluoromethyl ketones: Potent inhibitors of wild type and carbamate-insensitive G119S mutant Anopheles gambiae acetylcholinesterase

“…9b More commonly, these difluorinated ketones have been explored as inhibitors of serine proteases such as chymotrypsin, 14 α-lytic protease, 15 human leukocyte elastase, 15 and thrombin. 16 Perhaps due to the expectation that reduced electrophilicity would adversely impact inhibition potency, fluoromethyl ketones have (to our knowledge) not been reported as AChE inhibitors. Although 7 proved to be a very weak inhibitor of the serine protease chymotrypsin, 14 dipeptidyl aspartyl fluoromethyl ketones such as 8 can be potent inhibitors of cysteine proteases.…”

A Stereocontrolled Synthesis of Monofluoro Ketomethylene Dipeptide Isosteres

“…Incorporating α-fluorinated ketones within the peptide chain is less common. Difluorostatone analogues 3 have been studied as difluorinated dipeptide mimetics . Few examples of true difluoroketomethylene dipeptide isosteres 4 ( n = 2) are extant, and only a single example of a monofluoroketomethylene dipeptide isostere 4 ( n = 1) has been reported .…”