| Autor: |
Zhang B; Jiangmen Central Hospital, Jiangmen 529030, China., Zou ZK; Guangdong Provincial Key Laboratory of New Drug Screening, School of Pharmaceutical Science, Southern Medical University, Guangzhou 510515, P. R. China., Cai JF; Guangdong Provincial Key Laboratory of New Drug Screening, School of Pharmaceutical Science, Southern Medical University, Guangzhou 510515, P. R. China., Tan WM; Jiangmen Central Hospital, Jiangmen 529030, China., Chen JW; Jiangmen Central Hospital, Jiangmen 529030, China., Li WE; Jiangmen Central Hospital, Jiangmen 529030, China., Liang JN; Jiangmen Central Hospital, Jiangmen 529030, China., Wu WP; Jiangmen Central Hospital, Jiangmen 529030, China., Wang G; Jiangmen Central Hospital, Jiangmen 529030, China., Ruan XH; Jiangmen Central Hospital, Jiangmen 529030, China., Zhao PL; Guangdong Provincial Key Laboratory of New Drug Screening, School of Pharmaceutical Science, Southern Medical University, Guangzhou 510515, P. R. China. |
| Abstrakt: |
Phosphodiesterase 5 (PDE5) is a cGMP-specific hydrolytic enzyme and widely distributed in versatile tissues. PDE5 has been identified as a valid therapeutic target for treating erectile dysfunction and pulmonary arterial hypertension (PAH). Herein, a hit-to-lead structural optimizations were performed on the PDE1 inhibitor 10c , leading to compound 14b possessing great potency against PDE5A (IC 50 = 3 nM) with high selectivity over PDE1, PDE2, PDE3, PDE4, PDE7, PDE8, PDE9, PDE10, and PDE11 by more than 1125-fold, and remarkable safety properties. Furthermore, oral administration of 14b (5.0 mg/kg) exerted much better pharmacodynamics effects on both mPAP (mean pulmonary artery pressure) and RVHI (index of right ventricle hypertrophy) than sildenafil citrate (10.0 mg/kg) in a monocrotaline-induced PAH rat model. Overall, these results proposed a novel highly selective PDE5 inhibitor 14b which could serve as a potential candidate for treatment of PAH. |
