PHA121 is a highly potent, specific, and orally bioavailable small-molecule that competitively antagonizes the B2 receptor, demonstrating activity in bradykinin-mediated disease models. Pharvaris has completed IND-enabling studies of PHA121, anticipating first clinical entry in the early 2019.
Despite efforts by pharmaceutical and academic researchers over the last 30 years, orally bioavailable small-molecule B2 receptor antagonists have not been previously identified. Pharvaris identified a core binding motif for the B2 receptor with favorable physicochemical properties and optimized this core binding motif using deep structure-activity relationship analysis (SAR) and mutational studies.
The core motif contains structural features that uniquely interact with B2 receptor to improve the antagonist potency of our lead series into the sub-nanomolar range, the highest potency disclosed for a small molecule at this target. We further optimized physicochemical properties, metabolic stability, and oral absorption yielding orally active B2 receptor antagonists with high therapeutic potential.