681260-50-4Relevant articles and documents
Reductions in log P improved protein binding and clearance predictions enabling the prospective design of cannabinoid receptor (CB1) antagonists with desired pharmacokinetic properties
Ellsworth, Bruce A.,Sher, Philip M.,Wu, Ximao,Wu, Gang,Sulsky, Richard B.,Gu, Zhengxiang,Murugesan, Natesan,Zhu, Yeheng,Yu, Guixue,Sitkoff, Doree F.,Carlson, Kenneth E.,Kang, Liya,Yang, Yifan,Lee, Ning,Baska, Rose A.,Keim, William J.,Cullen, Mary Jane,Azzara, Anthony V.,Zuvich, Eva,Thomas, Michael A.,Rohrbach, Kenneth W.,Devenny, James J.,Godonis, Helen E.,Harvey, Susan J.,Murphy, Brian J.,Everlof, Gerry G.,Stetsko, Paul I.,Gudmundsson, Olafur,Johnghar, Susan,Ranasinghe, Asoka,Behnia, Kamelia,Pelleymounter, Mary Ann,Ewing, William R.
, p. 9586 - 9600 (2013)
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.
Triazolopyridine cannabinoid receptor 1 antagonists
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Page/Page column 78, (2008/06/13)
The present application describes compounds according to Formula I, pharmaceutical compositions comprising at least one compound according to Formula I and optionally one or more additional therapeutic agents, and methods of treatment using the compounds according to Formula I both alone and in combination with one or more additional therapeutic agents. The compounds have the following general formula: including all prodrugs, solvates, pharmaceutically acceptable salts and stereoisomers, wherein R1, R2, R3, R4 and R5 are described herein.
Triazolopyrimidine cannabinoid receptor 1 antagonists
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Page/Page column 42-43, (2010/11/25)
The present application describes compounds according to both Formulas I and II, pharmaceutical compositions comprising at least one compound according to either Formula I or II and optionally one or more additional therapeutic agents, and methods of treatment using the compounds according to Formulas I and II both alone and in combination with one or more additional therapeutic agents. The compounds have the following general formulas: including all prodrugs, solvates, pharmaceutically acceptable salts and stereoisomers, wherein R1, R2, R3, R4 and R5 are described herein.
