Hydroxamates: relationships between structure and plasma stability.
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.
Flipo
Marion
M
INSERM U761 Biostructures and Drug Discovery, Univ Lille Nord de France, Lille F-59006, France.
Charton
Julie
J
Hocine
Akila
A
Dassonneville
Sandrine
S
Deprez
Benoit
B
Deprez-Poulain
Rebecca
R
D000818:Animals; D004353:Drug Evaluation, Preclinical; D004355:Drug Stability; D004950:Esterases / Q000097:blood; D006207:Half-Life; D006801:Humans; D006868:Hydrolysis; D057927:Hydrophobic and Hydrophilic Interactions; D006877:Hydroxamic Acids / Q000097:blood / Q000138:chemical synthesis* / Q000737:chemistry; D010949:Plasma; D011355:Prodrugs / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
D006877:Hydroxamic Acids; D011355:Prodrugs; D004950:Esterases