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

Journal of Medicinal Chemistry
1992.0

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.

Knowledge Graph

Similar Paper

Pharmacokinetics of catechol cephalosporins. The effect of incorporating substituents into the catechol moiety on pharmacokinetics in a marmoset model
Journal of Medicinal Chemistry 1992.0
Structure-activity relations in cephalosporins prepared from penicillins. 2. Analogs of cephalexin substituted in the 3-methyl group
Journal of Medicinal Chemistry 1977.0
Substituent effects on reactivity and spectral parameters of cephalosporins
Journal of Medicinal Chemistry 1984.0
Oral absorption of cephalosproin antibiotics 2. Expanded structure-activity relationships of 7-arylacetamido-3-substituted cephalosporins
Journal of Medicinal Chemistry 1988.0
An examination of O-2-isocephems as orally absorbable antibiotics
Journal of Medicinal Chemistry 1988.0
Semisynthetic cephalosporins. Synthesis and structure-activity relations of 7-sulfonylacetamido-3-cephem-4-carboxylic acids
Journal of Medicinal Chemistry 1976.0
Oral absorption of cephalosporin antibiotics. 1. Synthesis, biological properties and oral bioavailability of 7-arylacetamido-3-chloro cephalosporins in animals
Journal of Medicinal Chemistry 1988.0
Synthesis and biological evaluation of a series of parenteral 3'-quaternary ammonium cephalosporins
Journal of Medicinal Chemistry 1990.0
Orally active esters of cephalosporin antibiotics. Synthesis and biological properties of acyloxymethyl esters of 7-(D-2-amino-2-phenylacetamido)-3-[5-methyl-(1,3,4-thiadiazol-2-yl)thiomethyl]-3-cephem-4-carboxylic acid
Journal of Medicinal Chemistry 1977.0
Synthesis and structure-activity relationship of new cephalosporins with amino heterocycles at C-7. Dependence of the antibacterial spectrum and .beta.-lactamase stability on the pKa of the C-7 heterocycle
Journal of Medicinal Chemistry 1991.0