Pharmacokinetics medicinal chemistry properties

The main medicinal chemistry properties of drugs that influence pharmacokinetics are ... 

Extensive medicinal chemistry optimization of potency, selectivity pharmacokinetic, and pharmacodynamic properties finally led to potent, selective, and orally bioavailable GSK-221149A, which is synthesized as shown on Scheme 17 [35, 37, 38]. Peptidic oxytocin receptor antagonists are currently used to treat preterm labor, the main reason for infant death. The peptide derivatives by their nature are not orally bioavailable but must be administered i.v. Surprisingly, the peptide derivatives are less potent and less selective against several related receptors than GSK-221149A with half the molecular weight [39]. 

Van der Waterbeemd, H., Smith, D.A., Beaumont, K. and Walker, D.K. (2001) Property-based design optimization of drug absorption and pharmacokinetics. Journal of Medicinal Chemistry, 44, 1313-1333. 

Pagliara, A., Testa, B., Carrupt, P.A., Jolliet, P., Morin, C., Morin, D., Urien, S., Tillement, J.P. and Rihoux, J.P. (1998) Molecular properties and pharmacokinetic behavior of cetirizine, a zwitterionic Hl-receptor antagonist. Journal of Medicinal Chemistry, 41, 853-863. 

Our studies with cyclic and acyclic diaminoketones provide useful examples of the impact of conformational constraint on inhibitory potency. Tabs. 5.1 and 5.2 show two analogue series that highlight the sometimes dramatic effects that cyclization can have. This modification can have equally dramatic effects on pharmacokinetic properties of the molecules as well. Conformationally restricted analogues have long been a goal of medicinal chemistry efforts such as the one reviewed here. Only recently has sufficient pharmacokinetic data become available to reveal the critical importance of constraint, in the form of reduced rotatable bond count, for improving oral bioavailability [5] as has been seen with compound (Fig. 5.4e) [19]. 

Property based design optimisation of drug absorption and pharmacokinetics. Journal of Medicinal Chemistry, 44, 1313-1333. 

Watkins, W.J., Landaverry, Y, Leger, R., Litman, R., Renau, T.E., Williams, N., Yen, R., Zhang, J.Z., Chamberland, S., Madsen, D., Griffith, D., Tembe, V., Huie, K., and Dudley, M.N. (2003) The relationship between physicochemical properties, in vitro activity and pharmacokinetic profiles of analogues of diamine-containing efflux pump inhibitors. Bioorganic Medicinal Chemistry Letters, 13 (23), 4241 244. 

Optimization covers many aspects in medicinal chemistry. The optimization of the afhnity and often selectivity for the biological target and the pharmacokinetic properties of a lead componnd are the primary goals of most preclinical research projects. Secondly, optimization strategies may be applied to... 

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