Apelin-13 is an endogenous peptidic agonist of the APJ receptor which has demonstrated increased cardiac function in heart failure patients. The low plasma stability of apelin-13 has precluded both oral administration and chronic dosing, therefore we focused on identification of a small molecule agonist to address these limitations. We report optimization of a HTS lead including detailed SAR of heterocyclic linkers (and substitution thereof) at the C3 position of the 4-hydroxypyridine-2-one core and for the phenyl ring at the C5 position. Incorporation of polar groups at the C6 position to improve physicochemical properties and increase bioavailability, re-optimization for potency and discovery of efficient synthetic methods will be described which enabled identification of our clinical candidate.

Optimization of 4-hydroxy-3-(heteroaryl)pyridine-2-one APJ receptor agonists for potency and oral PK profile

2019 Fall National Meeting

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