Catalyst Awardee

Project Description

Development of Small-Molecule Modulators of the Secretin Receptor as Novel Anti-Hypertensive Agents

Billy K.C. Chow, Ph.D. | The University of Hong Kong
Competition Sponsor:
Research Grants Council of the Hong Kong Special Administrative Region, China
Awardee year: 2022


Large segments of aging hypertensive patients are resistant to a wide range of conventional drugs and hence there is an urgent need for new initiatives to develop alternative treatments. Here, we develop the first small molecule-based Secretin receptor modulator (KSD179019), which not only has the similar blood pressure lowering effect as SCT peptide, but more importantly has a much longer half-life (~8 hours). Preclinical pharmacokinetics and toxicology studies revealed long bioavailability and low toxicity of this compound. Therefore, development of KSD179019 as a novel class of oral anti-hypertensive drug can be of critical importance, as it could tackle resistant hypertension. In addition, based on the recently CryoEM-resolved 3-D structure of human secretin receptor and the active pharmacophores of KSD179019, several analogues were designed and synthesized to further explore the structure-activity relationship. Our preliminary data suggest the presence of a functional structural core to be important for positive allosteric modulation of Secretin receptor. This observation is interesting and further studies could lead to improved and more potent small molecule drugs for Secretin receptor-involved health risks particularly for the aging population. Specifically, we believe that this project could potentially provide an important advancement in finding novel small molecule drugs for resistant hypertension by targeting Secretin receptor. The project describes the preclinical studies necessary to bring the project forward for GLP-labs and big pharma license agreements.

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