title: Inhibition of human leukocyte elastase. 3. Synthesis and activity of 3'-substituted cephalosporins.
abstract: Several 3'-substituted cephalosporin sulfones were synthesized from 3-(hydroxymethyl)cephalosporin, which was prepared by Ti(OiPr)4 hydrolysis of the corresponding acetate. A method was also developed to prepare a 3-vinylcephalosporin. Some of these compound were found to be potent time-dependent inhibitors of human leukocyte elastase (HLE). The HLE inhibitory activity was correlated with sigma 1 and it was concluded that the potency was determined by the electron-withdrawing ability as well as the size of the substituent. A mechanism for inhibition of HLE by cephalosporin sulfones is proposed.
authors.affiliation: Department of Medicinal Chemical Research, Merck Sharp and Dohme Research Laboratories, Rahway, New Jersey 07065.
authors.forename: S K
authors.initials: SK
authors.lastname: Shah
authors.forename: K A
authors.initials: KA
authors.lastname: Brause
authors.forename: G O
authors.initials: GO
authors.lastname: Chandler
authors.forename: P E
authors.initials: PE
authors.lastname: Finke
authors.forename: B M
authors.initials: BM
authors.lastname: Ashe
authors.forename: H
authors.initials: H
authors.lastname: Weston
authors.forename: W B
authors.initials: WB
authors.lastname: Knight
authors.forename: A L
authors.initials: AL
authors.lastname: Maycock
authors.forename: J B
authors.initials: JB
authors.lastname: Doherty
mesh_terms: D002511:Cephalosporins / Q000138:chemical synthesis* / Q000494:pharmacology; D055598:Chemical Phenomena; D002621:Chemistry; D006801:Humans; D019272:Leukocyte Elastase; D010196:Pancreatic Elastase / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship; D013450:Sulfones / Q000138:chemical synthesis / Q000494:pharmacology
chemical_list: D002511:Cephalosporins; D013450:Sulfones; D010196:Pancreatic Elastase; D019272:Leukocyte Elastase