Pulmonary arterial hypertension (PAH) has a poor prognosis and is associated with pulmonary vasoconstriction, right ventricular hypertrophy and right heart failure. Current therapies aim to reduce vasoconstriction but do not benefit the heart and more efficacious treatments are required. The peptide apelin signals through the apelin receptor to produce vasodilatation and cardiac inotropy, while its expression is decreased in PAH. Importantly, the apelin receptor is not down-regulated and infusion of apelin is beneficial in animal models1. As a peptide, apelin is not an optimal drug-like molecule owing to its lack of bioavailability, limited half-life and rapid internalisation of the receptor through β-arrestin signalling. We hypothesise that a G protein biased small molecule apelin agonist could replace the missing endogenous peptide to produce vasodilatation and an improvement in cardiac remodelling of the right ventricle without receptor desensitisation. We characterised, in vitro and in vivo, the pharmacology of a novel small molecule agonist, CMF-019, demonstrating G protein bias at the apelin receptor. In competition radioligand binding experiments in heart homogenates CMF-019 bound to human, rat and mouse apelin receptors with high affinity (pKi= 8.58±0.04, 8.49±0.04 and 8.71±0.06 respectively). In cell-based functional assays, whereas CMF-019 showed similar potency for the Gαi pathway to the endogenous agonist [Pyr1]apelin-13 (pD2=10.00±0.13 n=11/4 and pD2=9.34±0.15 n=8/4 respectively), in β-arrestin and internalisation assays it was much less potent (pD2=6.65±0.15 n=13/4 vs pD2=8.65±0.10 n=12/4 and pD2=6.16±0.21 n=6/2 vs pD2=9.28±0.10 n=6/2 respectively). Experiments were performed in triplicate where possible and results are expressed as mean±sem. For cell-based assays, n-values are given as the number of replicates/number of experiments. Bias analysis was performed using the methodology of van der Westhuizen et al. (2014)2 and bias factors of ~400 for signalling through the Gαi compared to the β-arrestin pathway and ~5800 compared to receptor internalisation were obtained. Normotensive male Sprague-Dawley rats (273 ± 6g) were induced and maintained under anaesthesia with inhaled isoflurane (3% and 1.5% respectively) carried by oxygen (1.5l/min) and a pressure-volume catheter placed in the left ventricle to measure cardiac parameters. Intravenously injected CMF-019 (2500µg) caused a significant increase in cardiac contractility (dP/dtMax, 833±152mmHg/s n=9) compared to saline (88.7±94.4mmHg/s n=3) (p<0.001, student’s t-test). CMF-019 is the first biased small molecule identified at the apelin receptor and displays activity in vivo. This molecule provides evidence that biased agonism can be developed in small molecules and provides a basis for the rational design of new biased apelin receptor agonists for the treatment of cardiovascular conditions such as PAH.