title: Inhibition of human leukocyte elastase. 1. Inhibition by C-7-substituted cephalosporin tert-butyl esters.
abstract: 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.
authors.affiliation: Department of Medicinal Chemical Research, Merck Sharp and Dohme Research Laboratories, Rahway, New Jersey 07065.
authors.forename: J B
authors.initials: JB
authors.lastname: Doherty
authors.forename: B M
authors.initials: BM
authors.lastname: Ashe
authors.forename: P L
authors.initials: PL
authors.lastname: Barker
authors.forename: T J
authors.initials: TJ
authors.lastname: Blacklock
authors.forename: J W
authors.initials: JW
authors.lastname: Butcher
authors.forename: G O
authors.initials: GO
authors.lastname: Chandler
authors.forename: M E
authors.initials: ME
authors.lastname: Dahlgren
authors.forename: P
authors.initials: P
authors.lastname: Davies
authors.forename: C P
authors.initials: CP
authors.lastname: Dorn
authors.forename: P E
authors.initials: PE
authors.lastname: Finke
mesh_terms: 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
chemical_list: D002264:Carboxylic Acids; D002511:Cephalosporins; D004952:Esters; D010196:Pancreatic Elastase; D019272:Leukocyte Elastase