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)-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 (Ca [2]⁺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.

apelin 受体 (APJ) 是心血管适应症的靶标。此前，我们已经鉴定了一种新型的吡唑类激动剂1 (( S )- N -(1-(cyclobutylamino)-1-oxo-5-(piperidin-1-yl)pentan-3-yl)-1-cyclopentyl-该 GPCR 的5-(2,6-二甲氧基苯基)-1 H-吡唑-3-甲酰胺盐酸盐)。对1进行系统修饰以产生具有改进效力和 ADME 特性的化合物。具有良好激动剂效力的口服生物可利用化合物47 (Ca [2] ⁺ EC ₅₀ = 24 nM, cAMPi EC ₅₀ =6.5 nM）和药代动力学特性（大鼠体内清除率为~20 ml/min/kg）。这种化合物大大降低了脑渗透，并且没有明显的脱靶责任。总之，已经确定了一种有效且选择性的 APJ 激动剂，适用于口服给药后外周组织中 APJ 的体内研究。