Peptidyl carbamates incorporating amino acid isosteres as novel elastase inhibitors

Abstract

The design and synthesis of 13 novel peptidyl carbamates are described. When tested for inhibitory activity toward porcine pancreatic elastase, trypsin, and chymotrypsin, six compounds were found to specifically inhibit elastase without affecting the other two serine proteases. All the active inhibitors had an amino acid isostere at the P1 position. Kinetic studies indicated that the inhibition was competitive with Ki values ranging from 4.23 X 10(-5) to 2.4 X 10(-6) M. The degree of inhibition was found to be dependent on the specificity of the peptide chain for the extended subsites on the enzyme as well as on the nature of P1'. Preliminary work on one inhibitor indicates that the inhibition is reversible and proceeds via the rapid formation of a strong enzyme-inhibitor complex, followed by slow acylation of the serine residue on the active site of the enzyme. Peptidyl carbamates represent a novel class of elastase inhibitors.

Kinetic evaluation of the solvolysis of isobutyl chloro- and chlorothioformate esters

“…Isobutyl chloroformate ( 1 ) and isobutyl chlorothioformate ( 2 ) have found use as specific precursors in novel synthetic routes for the preparation of peptidyl carbamate and thiocarbamate inhibitors of the enzyme elastase [66]. In Fig.…”

Crystal structure of phenyl N-(3,5-dimethylphenyl)carbamate

“…For example it tunes haemoglobin affinity for O 2 during physiological respiration (O'Donnell et al, 1979). Carbamates are widely employed as pharmacological and therapeutic agents (Greig et al, 2005), to inhibit different enzymes such as acetyl-and butyrylcholinesterases (Darvesh et al, 2008), cholesterol esterase (Hosie et al, 1987), elastase (Digenis et al, 1986), chymotrypsin (Lin et al, 2006) and fatty acid amide hydrolase (FAAH) (Kathuria et al, 2003). In the solid state, the carbamate group acts as both donor and acceptor in hydrogen bonding, favouring the formation of highly stable synthons.…”

Crystal structures of 4-chlorophenylN-(3,5-dinitrophenyl)carbamate and phenylN-(3,5-dinitrophenyl)carbamate

“…Carbamates are widely employed as pharmacological and therapeutic agents (Greig et al, 2005) to inhibit different enzymes, such as acetyl-and butyrylcholinesterases (Darvesh et al, 2008), cholesterol esterase (Hosie et al, 1987), elastase (Digenis et al, 1986,) chymotrypsin (Lin et al, 2006) and fatty acid amide hydrolase (FAAH) (Kathuria et al, 2003). The therapeutic exploitation of the endocannabinoid system with exogenous agonists is limited by the undesired side effects caused by indiscriminate activation of cannabinoid type-1 (CB1) receptors, particularly in the brain (Mechoulam & Parker, 2013).…”