[Epub ahead of print]
Reductions in log P improved protein binding and clearance predictions enabling the prospective design of cannabinoid receptor (CB1) antagonists with desired pharmacokinetic properties.
Ellsworth BA, Sher P, Wu X, Wu G, Sulsky RB, Gu Z, Murugesan N, Zhu Y, Yu G, Sitkoff DF, Carlson KE, Kang L, Yang Y, Lee N, Baska RA, Keim WJ, Cullen MJ, Azzara AV, Zuvich E, Thomas MA, Rohrbach KW, Devenny JJ, Godonis HE, Harvey SJ, Murphy BJ, Everlof GG, Stetsko PI,Gudmundsson O, Johnghar S, Ranasinghe A, Behnia K, Pelleymounter MA, Ewing WR.
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 dataset revealed a lack of correlation; however, when the dataset was limited to compounds with >5% free fraction, a more predictable correlation was observed. Compounds with log P between 3 to 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 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.
- PMID:
- 24182233
- [PubMed – as supplied by publisher]
