Inhibition of human leukocyte elastase. 1. Inhibition by C-7-substituted cephalosporin tert-butyl esters.
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.
Doherty
J B
JB
Department of Medicinal Chemical Research, Merck Sharp and Dohme Research Laboratories, Rahway, New Jersey 07065.
Ashe
B M
BM
Barker
P L
PL
Blacklock
T J
TJ
Butcher
J W
JW
Chandler
G O
GO
Dahlgren
M E
ME
Davies
P
P
Dorn
C P
CP
Finke
P E
PE
D002264:Carboxylic Acids / Q000138:chemical synthesis*; D002511:Cephalosporins / Q000138:chemical synthesis* / Q000494:pharmacology; D055598:Chemical Phenomena; D002621:Chemistry; D004952:Esters / Q000138:chemical synthesis* / Q000494:pharmacology; D006801:Humans; D019272:Leukocyte Elastase; D010196:Pancreatic Elastase / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship
D002264:Carboxylic Acids; D002511:Cephalosporins; D004952:Esters; D010196:Pancreatic Elastase; D019272:Leukocyte Elastase