Design and Development of a Macrocyclic Series Targeting Phosphoinositide 3-Kinase δ.

A macrocyclization approach has been explored on a series of benzoxazine phosphoinositide 3-kinase δ inhibitors, resulting in compounds with improved potency, permeability, and clearance while maintaining good solubility. The thermodynamics of binding was explored via surface plasmon resonance, and the binding of lead macrocycle was found to be almost exclusively entropically driven compared with progenitor , which demonstrated both enthalpic and entropic contributions. The pharmacokinetics of macrocycle was also explored , where it showed reduced clearance when compared with the progenitor . This work adds to the growing body of evidence that macrocyclization could provide an alternative and complementary approach to the design of small-molecule inhibitors, with the potential to deliver differentiated properties.