Journal article
Reductions in log P Improved Protein Binding and Clearance Predictions Enabling the Prospective Design of Cannabinoid Receptor (CB1) Antagonists with Desired Pharmacokinetic Properties
Journal of medicinal chemistry, v 56(23), pp 9586-9600
12 Dec 2013
PMID: 24182233
Featured in Collection : UN Sustainable Development Goals @ Drexel
Abstract
Several strategies have been employed to reduce the long in vivo half-life of our lead CB1 antagonist, triazolopyridazinone 3, to differentiate the pharmacokinetic profile versus the lead clinical compounds. An in vitro and in vivo clearance data set revealed a lack of correlation; however, when compounds with <5% free fraction were excluded, a more predictable correlation was observed. Compounds with log P between 3 and 4 were likely to have significant free fraction, so we designed compounds in this range to give more predictable clearance values. This strategy produced compounds with desirable in vivo half-lives, ultimately leading to the discovery of compound 46. The progression of compound 46 was halted due to the contemporaneous marketing and clinical withdrawal of other centrally acting CB1 antagonists; however, the design strategy successfully delivered a potent CB1 antagonist with the desired pharmacokinetic properties and a clean off-target profile.
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Details
- Title
- Reductions in log P Improved Protein Binding and Clearance Predictions Enabling the Prospective Design of Cannabinoid Receptor (CB1) Antagonists with Desired Pharmacokinetic Properties
- Creators
- Bruce A. Ellsworth - Bristol-Myers Squibb (United States)Philip M. Sher - Bristol-Myers Squibb (United States)Ximao Wu - Bristol-Myers Squibb (United States)Gang Wu - Bristol-Myers Squibb (United States)Richard B. Sulsky - Bristol-Myers Squibb (United States)Zhengxiang Gu - Bristol-Myers Squibb (United States)Natesan Murugesan - Bristol-Myers Squibb (United States)Yeheng Zhu - Bristol-Myers Squibb (United States)Guixue Yu - Bristol Myers Squibb Co, Res & Dev, Princeton, NJ 08543 USADoree F. Sitkoff - Bristol-Myers Squibb (United States)Kenneth E. Carlson - Bristol-Myers Squibb (United States)Liya Kang - Bristol-Myers Squibb (United States)Yifan Yang - Bristol-Myers Squibb (United States)Ning Lee - Bristol-Myers Squibb (United States)Rose A. Baska - Bristol-Myers Squibb (United States)William J. Keim - Bristol-Myers Squibb (United States)Mary Jane Cullen - Bristol-Myers Squibb (United States)Anthony V. Azzara - Bristol-Myers Squibb (United States)Eva Zuvich - Bristol-Myers Squibb (United States)Michael A. Thomas - Bristol-Myers Squibb (United States)Kenneth W. Rohrbach - Bristol-Myers Squibb (United States)James J. Devenny - Bristol-Myers Squibb (United States)Helen E. Godonis - Bristol-Myers Squibb (United States)Susan J. Harvey - Bristol-Myers Squibb (United States)Brian J. Murphy - Bristol-Myers Squibb (United States)Gerry G. Everlof - Bristol-Myers Squibb (United States)Paul I. Stetsko - Bristol-Myers Squibb (United States)Olafur Gudmundsson - Bristol-Myers Squibb (United States)Susan Johnghar - Bristol-Myers Squibb (United States)Asoka Ranasinghe - Bristol-Myers Squibb (United States)Kamelia Behnia - Bristol-Myers Squibb (United States)Mary Ann Pelleymounter - Bristol-Myers Squibb (United States)William R. Ewing - Bristol-Myers Squibb (United States)
- Publication Details
- Journal of medicinal chemistry, v 56(23), pp 9586-9600
- Publisher
- Amer Chemical Soc
- Number of pages
- 15
- Resource Type
- Journal article
- Language
- English
- Academic Unit
- Pharmacology and Physiology
- Web of Science ID
- WOS:000328529700017
- Scopus ID
- 2-s2.0-84890451751
- Other Identifier
- 991021902532304721
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InCites Highlights
Data related to this publication, from InCites Benchmarking & Analytics tool:
- Web of Science research areas
- Chemistry, Medicinal