Synthesis and Characterization of an Orally Bioavailable Small Molecule Agonist of the Apelin Receptor

113 Pages Posted: 23 Mar 2022

See all articles by Sanju Narayanan

Sanju Narayanan

RTI International

Donghua Dai

affiliation not provided to SSRN

Ravi Kumar Vyas Devambatla

affiliation not provided to SSRN

Vincent Albert

Paraza Pharma Inc

Nicolas Bruneau-Latour

affiliation not provided to SSRN

Vineetha Vasukuttan

RTI International

Stephane Ciblat

affiliation not provided to SSRN

Kenneth Rehder

RTI International

Scott Runyon

RTI International

Rangan Maitra

RTI International

Abstract

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-(2,6-dimethoxyphenyl)-1 H -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 (Ca 2+ EC 50  = 24 nM, cAMPi EC 50 = 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.

Keywords: Apelin receptor, APJ, aplnr, agonist, pyrazole, cardiovascular, oral, drug discovery

Suggested Citation

Narayanan, Sanju and Dai, Donghua and Devambatla, Ravi Kumar Vyas and Albert, Vincent and Bruneau-Latour, Nicolas and Vasukuttan, Vineetha and Ciblat, Stephane and Rehder, Kenneth and Runyon, Scott and Maitra, Rangan, Synthesis and Characterization of an Orally Bioavailable Small Molecule Agonist of the Apelin Receptor. Available at SSRN: https://ssrn.com/abstract=4064345 or http://dx.doi.org/10.2139/ssrn.4064345

Sanju Narayanan

RTI International ( email )

PO Box 12194
Washington, DC 20036-3209
United States

Donghua Dai

affiliation not provided to SSRN ( email )

No Address Available

Ravi Kumar Vyas Devambatla

affiliation not provided to SSRN ( email )

No Address Available

Vincent Albert

Paraza Pharma Inc ( email )

Nicolas Bruneau-Latour

affiliation not provided to SSRN ( email )

No Address Available

Vineetha Vasukuttan

RTI International ( email )

Stephane Ciblat

affiliation not provided to SSRN ( email )

No Address Available

Kenneth Rehder

RTI International ( email )

PO Box 12194
Washington, DC 20036-3209
United States

Scott Runyon

RTI International ( email )

PO Box 12194
Washington, DC 20036-3209
United States

Rangan Maitra (Contact Author)

RTI International ( email )

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