Pharmacokinetics of catechol cephalosporins. The effect of incorporating substituents into the catechol moiety on pharmacokinetics in a marmoset model

J Med Chem. 1992 Jul 10;35(14):2643-51. doi: 10.1021/jm00092a015.

Abstract

Two series of cephalosporins A and B have been synthesized, bearing at C-3' catechols substituted with various electron withdrawing groups (Y) and differing links (X), and were evaluated for their in vitro antibacterial activity and their pharmacokinetics in marmosets. Compounds in series A, bearing an isobutyric oxime substituent, proved to be highly active against Gram-negative organisms and were especially noteworthy for showing long elimination phase (beta) half-lives in marmosets. It was established that introduction of electron withdrawing substituents greatly increased the beta half-lives of compounds (5, X = NHCO, Y = H, t1/2 = 1.25 h, AUC = 27 mg/h per L; 11, X = NHCO, Y = 5-Cl, t1/2 = 4.5 h, AUC = 638 mg/h per L) and that the nature of the link also influenced t1/2, the highest values being obtained when X = NHCO and OCO. Acidities (pKa values) of the substituted catechols were measured, and relationships between the acidities and half-lives were evaluated. Thus it was established that the more acidic catechols gave the longest half-lives (12, X = NHCO, Y = 2,5-Cl2, t1/2 = 8.2 h, AUC = 461 mg/h per L). Further elaboration of the catechol to bicyclic systems maintained good pharmacokinetics when the pKa was sufficiently acidic.

MeSH terms

  • Animals
  • Blood Proteins / metabolism
  • Callithrix
  • Catechols / chemistry
  • Catechols / pharmacokinetics*
  • Catechols / pharmacology
  • Cephalosporins / chemistry
  • Cephalosporins / pharmacokinetics*
  • Cephalosporins / pharmacology
  • Female
  • Half-Life
  • Male
  • Mice
  • Pseudomonas aeruginosa / drug effects
  • Structure-Activity Relationship

Substances

  • Blood Proteins
  • Catechols
  • Cephalosporins