Conformational restriction bioavailability

Recently, much attention has been directed toward the synthesis of peptidomimetics. These compounds can replace native peptides in the interaction with receptors. They showed increased metabolic stability, better bioavailability, and longer duration of action than native peptides, thus displaying favorable pharmacological properties [52-54]. In this sense, the design and synthesis of conformationally restricted peptidomimetics is an important approach toward improving the potency, selectivity, and metabolic stability of peptide based chugs. 

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]. 

Thrombin inhibitors like o-Phe-Pro-Arg aldehyde have been known for a long time. However, the compounds lacked oral bioavailability. A semi-rational approach was adopted to modify Pj to Pj positions to improve the potency, selectivity and pharmacokinetic properties. Changes in individual positions were followed by multiple changes and synthesis of conformationally restricted analogues, Substitution of the C-terminal arginine aldehyde moiety (Pj position) by p-amidinobenzylamine gave... 

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