Hydroxamates: relationships between structure and plasma stability.

Publisher: American Chemical Society Country of Publication: United States NLM ID: 9716531 Publication Model: Print Cited Medium: Internet ISSN: 1520-4804 (Electronic) Linking ISSN: 00222623 NLM ISO Abbreviation: J Med Chem Subsets: MEDLINE

Publication: Washington Dc : American Chemical Society
Original Publication: [Easton, Pa.] : American Chemical Society, [c1963-

Hydroxamic Acids/*chemical synthesis; Animals ; Drug Evaluation, Preclinical ; Drug Stability ; Esterases/blood ; Half-Life ; Humans ; Hydrolysis ; Hydrophobic and Hydrophilic Interactions ; Hydroxamic Acids/blood ; Hydroxamic Acids/chemistry ; Plasma ; Prodrugs/chemical synthesis ; Prodrugs/chemistry ; Prodrugs/metabolism ; Rats ; Rats, Sprague-Dawley ; Stereoisomerism ; Structure-Activity Relationship

Hydroxamates are valuable tools for chemical biology as well as interesting leads for medicinal chemistry. Although many hydroxamates display nanomolar activities against metalloproteases, only three hydroxamates have reached the market, among which is the HDAC inhibitor vorinostat. Failures in development are generally attributed to lack of selectivity, toxicity, or poor stability. To help medicinal chemists with respect to plasma stability, we have performed the first and preliminary study on structure-plasma stability for hydroxamates. We define some structural rules to predict or improve the plasma stability in the preclinical stage.

0 (Hydroxamic Acids)
0 (Prodrugs)
EC 3.1.- (Esterases)

Date Created: 20091014 Date Completed: 20091215 Latest Revision: 20101118

20221213

10.1021/jm900648x

19821586