221052-03-5Relevant academic research and scientific papers
N-[2,2-dimethyl-3-(N-(4-cyanobenzoyl)amino)nonanoyl]-L-phenylalanine ethyl ester as a stable ester-type inhibitor of chymotrypsin-like serine proteases: Structural requirements for potent inhibition of α-chymotrypsin
Iijima, Kiyoko,Katada, Jun,Yasuda, Emiko,Uno, Isao,Hayashi, Yoshio
, p. 312 - 323 (2007/10/03)
We introduce a new potent inhibitor, N-[2,2-dimethyl-3-(N-(4- cyanobenzoyl)amino)nonanoyl]n-phenylalanine ethyl ester (3), which preferentially inhibits serine proteases belonging to a chymotrypsin superfamily. This inhibitor, despite consisting of a stable ethyl ester structure, showed strong inhibitory activities toward bovine α-chymotrypsin, human cathepsin G, and porcine elastase by acting as an acylating agent. The calculated inactivation rate constant (k(inact)) and enzyme-inhibitor dissociation constant (K(i)) against α-chymotrypsin were 0.0028 s-1 and 0.0045 μM, respectively (k(inact)/K(i) = 630 000 M-1 s-1). These kinetic parameters indicate that this inhibitor is one of the most powerful α- chymotrypsin inactivators ever reported. On the basis of structure-activity relationship (SAR) and structure-stability relationship studies of analogues of 3, which were modified in three parts of the molecule, i.e., the 4- cyanophenyl group, β-substituent at the β-amino acid residue, and ester structure, we suggest that the potent inhibitory activity of 3 is due to the following structural features: (1) the ethyl ester which enforces specific acyl-enzyme formation, (2) the n-hexyl group at the β-position and 4- cyanophenyl group which stabilize the acyl-enzyme, and (3) the phenylalanine residue which functions for the specific recognition of S1 site in the enzyme. In particular, the action of 3 as a potent inhibitor, but poor substrate, can be ascribed largely to the very slow deacylation rate depending on the structure factors cited in feature 2. The results of inhibition by 3 and its analogues against different serine proteases such as chymase, cathepsin G, and elastase suggest that these compounds recognize common parts in the active sites among these chymotrypsin-like serine proteases, and 3 is one of the most suitable structures to recognize those common parts. Our results provide an intriguing basis for further developments in the design of a stable ester-based selective serine protease inhibitor.
