The in vivo utility, or """"""""drugability"""""""", of a compound requires the molecule to reach the target tissues at sufficient concentrations to elicit the desired biological effect. This includes the need for a simple route of administration. The Drug Metabolism and Pharmacokinetics (DMPK) project aims to rapidly determine key compound liabilities and communicate these with the other project heads to facilitate the rapid optimization of the lead molecules. Past industry strategies emphasizing early optimization of target potency and selectivity without metabolism data resulted in 40% of molecules entering the clinic in 1991 failing for PK or bioavailability reasons. PK failures have been reduced 4-fold due to the early incorporation of DMPK. in addition to metabolism and elimination, pharmacodynamic factors, such as plasma protein binding, solubility, and permeability will influence the ultimate efficacy. Additional studies to determine the potential for drug-drug interactions or reactive intermediate formation will help promote the safest molecules In order to provide this type of crucial information, DMPK studies will be performed throughout the compound optimization phase. Information about the metabolic stability and disposition of the orexin receptor antagonists in vitro and in vivo will be rapidly communicated back to the chemists to facilitate compound optimization. At the early stages of the project, during which time hits are being identified and prioritized, measurements of gross features of bioavailability and metabolism will be made to eliminate candidate compounds. As the project matures, more intensive measurements of compound parameters will be made on a smaller numbers of refined lead structures to guide their development.
Orexin antagonists offer exciting potential as treatments for nicotine dependence. Successfully translating this potential into the discovery of an efficacious drug requires an early understanding the drug metabolism and pharmacokinetic so the whole molecule can be optimized instead of just the biochemical or cellular potency.
| Wall, Teagan R; Henderson, Brandon J; Voren, George et al. (2017) TC299423, a Novel Agonist for Nicotinic Acetylcholine Receptors. Front Pharmacol 8:641 |
| Patouret, Remi; Kamenecka, Theodore M (2016) Synthesis of 2-aryl-2H-tetrazoles via a regioselective [3+2] cycloaddition reaction. Tetrahedron Lett 57:1597-1599 |
| Doebelin, Christelle; He, Yuanjun; Kamenecka, Theodore M (2016) Multigram-scale Synthesis of Enantiopure 3,3-Difluoroproline. Tetrahedron Lett 57:5658-5660 |
| Robinson, James D; McDonald, Patricia H (2015) The orexin 1 receptor modulates kappa opioid receptor function via a JNK-dependent mechanism. Cell Signal 27:1449-56 |
| Jiang, Rong; Song, Xinyi; Bali, Purva et al. (2012) Disubstituted piperidines as potent orexin (hypocretin) receptor antagonists. Bioorg Med Chem Lett 22:3890-4 |
| Harmey, Dympna; Griffin, Patrick R; Kenny, Paul J (2012) Development of novel pharmacotherapeutics for tobacco dependence: progress and future directions. Nicotine Tob Res 14:1300-18 |
