Sun, Weimei published the artcileTargeting enteropeptidase with reversible covalent inhibitors to achieve metabolic benefits, Recommanded Product: 3-Chloro-4-hydroxyphenylacetic acid, the publication is Journal of Pharmacology and Experimental Therapeutics (2020), 375(3), 510-521, database is CAplus and MEDLINE.
Inhibition of the serine protease enteropeptidase (EP) opens a new avenue to the discovery of chemotherapeutics for the treatment of metabolic diseases. Camostat has been used clin. for treating chronic pancreatitis in Japan; however, the mechanistic basis of the observed clin. efficacy has not been fully elucidated. We demonstrate that camostat is a potent reversible covalent inhibitor of EP, with an inhibition potency (kinact/KI) of 1.5 x 104 M-1s-1. High-resolution liquid chromatog.-mass spectrometry (LC-MS) showed addition of 161.6 Da to EP after the reaction with camostat, consistent with insertion of the carboxyphenylguanidine moiety of camostat. Covalent inhibition of EP by camostat is reversible, with an enzyme reactivation half-life of 14.3 h. Formation of a covalent adduct was further supported by a crystal structure resolved to 2.19 Å, showing modification of the catalytic serine of EP by a close analog of camostat, leading to formation of the carboxyphenylguanidine acyl enzyme identical to that expected for the reaction with camostat. Of particular note, minor structural modifications of camostat led to changes in the mechanism of inhibition. We observed from other studies that sustained inhibition of EP is required to effect a reduction in cumulative food intake and body weight, with concomitant improved blood glucose levels in obese and diabetic leptin-deficient mice. Thus, the structure-activity relationship needs to be driven by not only the inhibition potency but also the mechanistic and kinetic characterization. Our findings support EP as a target for the treatment of metabolic diseases and demonstrate that reversible covalent EP inhibitors show clin. relevant efficacy.
Journal of Pharmacology and Experimental Therapeutics published new progress about 33697-81-3. 33697-81-3 belongs to chlorides-buliding-blocks, auxiliary class Chloride,Carboxylic acid,Benzene,Phenol, name is 3-Chloro-4-hydroxyphenylacetic acid, and the molecular formula is C12H10F2Si, Recommanded Product: 3-Chloro-4-hydroxyphenylacetic acid.
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