RTI uses cookies to offer you the best experience online. By clicking “accept” on this website, you opt in and you agree to the use of cookies. If you would like to know more about how RTI uses cookies and how to manage them please view our Privacy Policy here. You can “opt out” or change your mind by visiting: http://optout.aboutads.info/. Click “accept” to agree.
Synthesis and characterization of an orally bioavailable small molecule agonist of the apelin receptor
Narayanan, S., Dai, D., Devambatla, R. K. V., Albert, V., Bruneau-Latour, N., Vasukuttan, V., Ciblat, S., Rehder, K., Runyon, S. P., & Maitra, R. (2022). Synthesis and characterization of an orally bioavailable small molecule agonist of the apelin receptor. Bioorganic and Medicinal Chemistry, 66, Article 116789. https://doi.org/10.1016/j.bmc.2022.116789
The apelin receptor (APJ) is a target for cardiovascular indications. Previously, we had identified a novel pyrazole-based agonist 1 ((S)-N-(1-(cyclobutylamino)-1-oxo-5-(piperidin-1-yl)pentan-3-yl)-1-cyclopentyl-5-(2,6dimethoxyphenyl)-1H-pyrazole-3-carboxamide hydrochloride) of this GPCR. Systematic modification of 1 was performed to produce compounds with improved potency and ADME properties. Orally bioavailable compound 47 with favorable agonist potency (Ca2+EC50 = 24 nM, cAMPi EC50 = 6.5 nM) and pharmacokinetic properties (clearance ~20 mL/min/kg in rats) was identified. This compound has vastly reduced brain penetration and is devoid of significant off-target liability. In summary, a potent and selective APJ agonist suitable for in vivo studies of APJ in peripheral tissues after oral administration has been identified.
