208397-01-7

Upstream product

• 99300-38-6 4-cyanobenzoic acid N-hydroxysuccinimide ester 
• 590-86-3 isovaleraldehyde 
• 208396-92-3 4-isobutyl-3,3-dimethyl-2-azetidinone 

Downstream Products

• 1026675-93-3 {1-[3-(4-Carbamimidoyl-benzoylamino)-2,2,5-trimethyl-hexanoyl]-piperidin-4-yl}-acetic acid methyl ester 
• 208397-08-4 {1-[3-(4-Cyano-benzoylamino)-2,2,5-trimethyl-hexanoyl]-piperidin-4-yl}-acetic acid methyl ester 

Relevant 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

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.

GPIIb/IIIa integrin antagonists with the new conformational restriction unit, trisubstituted β-amino acid derivatives, and a substituted benzamidine structure

Ethyl N-[3-(2-fluor-4-(thiazolidin-3-y](imino)methyl)benzoyl)amino-2,2- dimethylpentanoyl]piperidine-4-acetate 40 (NSL-96184) is a highly potent and orally active fibrinogen receptor antagonist, which is characterized by the presence of the trisubstituted β-amino acid residue, 3-ethyl-2,2-dimethyl- β-alanine. This compound was developed on the basis of the SAR study of N- [3-N-4-amidinobenzoyl)amino-2,2-dimethyl-3-phenylpropionyl]piperidine-4- acetic acid 1 (NSL-95301) with the derivatization focused on the central trisubstituted β-amino acid unit as well as the basic amidinobenzoyl unit, and the esterification of the carboxyl group for prodrug composition. Compound 1, which was reported in our previous study, was discovered by the application of combinatorial chemistry. The molecular modeling study suggests that the trisubstituted β-amino acid unit is responsible for fixing the molecule to its active conformation. Compound 40 showed an excellent profile in the in vitro and in vivo studies for its human platelet aggregation inhibitory activity and oral availability in guinea pigs. This oral availability largely depends on the modification of the amidino group with a cyclic secondary amine, i.e., thiazolidine in 40. In in vivo studies, the onset of the antiplatelet action of 40 is very fast after oral administration, whereas its duration of action is relatively short. These results suggest that 40 has an excellent therapeutic potential, especially for antithrombotic treatment in the acute phase. 3-Substituted-2,2-dimethyl- β-amino acid residues would serve as new and useful linear templates to restrict the conformational flexibility of peptidomimetics.