Reductions in log P Improved Protein Binding and Clearance Predictions Enabling the Prospective Design of Cannabinoid Receptor (CB1) Antagonists with Desired Pharmacokinetic Properties

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.

Investigations on the 4-Quinolone-3-carboxylic Acid Motif. 7. Synthesis and Pharmacological Evaluation of 4-Quinolone-3-carboxamides and 4-Hydroxy-2-quinolone-3-carboxamides as High Affinity Cannabinoid Receptor 2 (CB2R) Ligands with Improved Aqueous Solubility

“…While a high attrition rate in drug research and development can be due in principle to a number of factors, in the case of cannabinoids, and particularly for CB2R-targeting compounds, inadequate drug-likeness may be a major issue. Using CB2R agonists/inverse agonists in vivo is challenging, as these compounds are inherently very lipophilic and usually show not optimal pharmacokinetic profile, being characterized by high binding to plasma proteins, long half-life, low bioavailability, and off-target effects . Structural optimization of CB2R ligands aimed at balancing lipophilicity (necessary to reach the target receptor) and aqueous solubility (necessary to ensure acceptable bioavailability) is a very challenging endeavor .…”

“…Using CB2R agonists/inverse agonists in vivo is challenging, as these compounds are inherently very lipophilic 4 and usually show not optimal pharmacokinetic profile, being characterized by high binding to plasma proteins, long half-life, low bioavailability, and off-target effects. 5 Structural optimization of CB2R ligands aimed at balancing lipophilicity (necessary to reach the target receptor) and aqueous solubility (necessary to ensure acceptable bioavailability) is a very challenging endeavor. 6 The development of tailored system for delivery and specific targeting of these molecules, whenever applicable, is a strategy that can be pursued to overcome their limitations in terms of physicochemical and pharmacokinetic properties.…”

The syntheses of isotopically labelled CB‐1 antagonists for the treatment of obesity

“…Understanding the connectivity between CB‐1 and weight gain has important practical implications because blocking the CB‐1 receptor was thought to offer a promising therapeutic approach to treating obesity . From Bristol‐Myers Squibb Discovery Chemistry efforts for the CB‐1 program, BMS‐725519, BMS‐811064, and BMS‐812204 emerged as potent and selective CB‐1 antagonists. They work by blocking endogenous cannabinoids binding to neuronal CB‐1 receptors.…”

Development of Quinazoline/Pyrimidine-2,4(1H,3H)-diones as Agonists of Cannabinoid Receptor Type 2

“…Ellsworth et al have described their efforts to improve the pharmacokinetic properties within their chemical series via reductions in logP. 13 Recently, a series of quinolone-2,4(1H,3H)-diones has been reported to be CB2 ligands by our group. 14 Compound 1 (Figure 1), a potent CB2 agonist, has been demonstrated to alleviate clinical symptoms of experimental autoimmune encephalomyelitis and protect the CNS from immune damage.…”

“…Hence, reducing the logP value without compromising activity may be a strategy to obtain promising CB2 ligands. Ellsworth et al have described their efforts to improve the pharmacokinetic properties within their chemical series via reductions in logP …”