This technology includes the development of selective P2Y14R antagonists for the treatment of asthma, sterile inflammation of the kidney, diabetes, and neurodegeneration. The P2Y14 receptor (P2Y14R) is a target for the treatment of inflammatory diseases, including pulmonary and renal conditions. Selective P2Y14R antagonists have demonstrated efficacy in animal models of asthma, pain, diabetes, and acute kidney injury. However, the prototypical antagonist is not optimal for in vivo administration, as it displays a low oral bioavailability. This invention includes P2Y14R antagonists that contain sterically constrained, bridged piperidine modifications or uncharged bioisosteres of the piperidine moiety. This approach aligns with a general trend to improve druglikeness in medicinal chemistry by adding three-dimensionality to otherwise flat molecules. We also invented prodrugs of the most potent analogs that display significant in vivo activity.
A selective antagonist for the P2Y14 receptor is a potentially useful treatment for patients with neuropathic pain. Current FDA-approved drugs for the treatment of neuropathic pain are not very effective.