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Inhibition of human leukocyte elastase. 1. Inhibition by C-7-substituted cephalosporin tert-butyl esters. 1990
J B Doherty, and
B M Ashe, and
P L Barker, and
T J Blacklock, and
J W Butcher, and
G O Chandler, and
M E Dahlgren, and
P Davies, and
C P Dorn, and
P E Finke
Department of Medicinal Chemical Research, Merck Sharp and Dohme Research Laboratories, Rahway, New Jersey 07065.
Time-dependent inhibitors of the enzyme human leukocyte elastase have been developed based on the cephem nucleus. A series of cephalosporin tert-butyl esters has been examined, and the activity of these compounds has been found to be very sensitive to C-7 substituents, with small, alpha-oriented, electron-withdrawing groups showing greatest activity. Additionally, the oxidation state of the sulfur atom has been found to play a role in potency, with sulfones showing considerably greater activity than the corresponding sulfides or beta-sulfoxides. The alpha-sulfoxides were inactive.
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