Improving the odds of success in drug discovery: choosing the best compounds for in vivo toxicology studies.
A set of molecules that advanced into exploratory animal toxicology studies (two species) was examined to determine what properties contributed to success in these safety studies. Compounds were rigorously evaluated across numerous safety end points and classified as "pass" if a suitable in vivo therapeutic index (TI) was achieved for advancement into regulatory toxicology studies. The most predictive end point contributing to compound survival was a predicted human efficacious concentration (Ceff) of ≤250 nM (total drug) and ≤40 nM (free drug). This trend held across a wide range of CNS modes of action, encompassing targets such as enzymes, G-protein-coupled receptors, ion channels, and transporters.
Pfizer Worldwide Research and Development , 700 Main Street, Cambridge, Massachusetts 02139, United States.
Travis T
TT
Wager
Bethany L
BL
Kormos
Joseph T
JT
Brady
Yvonne
Y
Will
Michael D
MD
Aleo
Donald B
DB
Stedman
Max
M
Kuhn
Ramalakshmi Y
RY
Chandrasekaran
D000818:Animals; D002491:Central Nervous System Agents / Q000009:adverse effects; D004285:Dogs; D055808:Drug Discovery / Q000379:methods*; D064420:Drug-Related Side Effects and Adverse Reactions; D006801:Humans; D008055:Lipids / Q000737:chemistry; D008252:Macaca fascicularis; D019055:No-Observed-Adverse-Effect Level; D051381:Rats
D002491:Central Nervous System Agents; D008055:Lipids