Solubility-Driven Lead Optimization of PAR4 Antagonists and Evaluation of a Phosphate Ester Prodrug Delivery Strategy

Lead optimization of PAR4 antagonist 1 was carried out with the aim of improving the aqueous solubility to obviate the need for enabled formulations. Structural modifications, including deannulation and introduction of polar functionality, led to lead compound 32. Compound 32 demonstrated potent ex vivo and in vivo platelet aggregation inhibition and oral exposure when dosed from an enabled solubilizing PEG formulation. It was demonstrated that when a phosphate ester prodrug was appended to the terminal hydroxy group of 32 to obtain compound 44, the aqueous thermodynamic solubility in 50 mM phosphate buffer improved >1200-fold. Oral dosing of 44 in rats delivered the parent compound 32 with 44% relative bioavailability to the enabled parent. Although this represented a reduction in total exposure relative to dosing the parent from the enabled formulation, likely due to incomplete absorption or phosphate ester cleavage, the prodrug successfully provided systemic coverage without solubilizing excipients.