Pyrazoles dehydrogenase inhibitor

Some of the most important aromatic pyrazoles with biological activity are shown in Table 38. Pyrazole itself and several A-unsubstituted pyrazoles are inhibitors and deactivators of liver alcohol dehydrogenase (79JMC356, 79ACS(B)483, B-79MI40414, 82ACS(B)10l). 

Steric effects and FMO control have been combined in an elegant way to achieve regiospecific synthesis of pyrazole inhibitors of dihydroorotate dehydrogenase <2006SL901>. When the size of the propargylic acid ester 86 is increased from ethyl to diphenylmethyl, pyrazole 87 is formed from compound 85 regiospecifically (Scheme 3 Table 4) <2006H(68)1007>. 

The initial rates (v in juM/min) of liver alcohol dehydrogenase-catalyzed ethanal reduction are measured in the presence of pyrazole as an inhibitor at the constant concentration of NADH (0.02 M) and the constant concentration of ethanal (2.0 mM), respectively. Propose respective inhibition types and estimate their inhibition constants. 

Human alcohol dehydrogenase isoenzymes have been divided into three classes. Class I isoenzymes contain a, p, yl, and y2 subunit isoenzymes, are cationic at neutral pH, and are strongly inhibited by substituted pyrazole inhibitors. Class II isoenzymes contain the 7i isoenzyme subunit, are cationic at neutral pH, and are relatively insensitive to pyrazole inhibition. Class III isoenzymes contain the X subunit, are anionic at neutral pH and are insensitive to pyrazole inhibitors. 

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