6IWI

Crystal structure of PDE5A in complex with a novel inhibitor

Summary for 6IWI

• Entry DOI: 10.2210/pdb6iwi/pdb
• Descriptor: cGMP-specific 3',5'-cyclic phosphodiesterase, MAGNESIUM ION, ZINC ION, ... (5 entities in total)
• Functional Keywords: pde5a, inhibitor, complex structure, hydrolase
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 1
• Total formula weight: 40622.37

Authors

Zhang, X.L.,Xu, Y.C. (deposition date: 2018-12-05, release date: 2019-12-11, Last modification date: 2024-03-27)

Primary citation

Wang, Z.,Jiang, X.,Zhang, X.,Tian, G.,Yang, R.,Wu, J.,Zou, X.,Liu, Z.,Yang, X.,Wu, C.,Shi, J.,Li, J.,Suo, J.,Wang, Y.,Zhang, R.,Xu, Z.,Gong, X.,He, Y.,Zhu, W.,Aisa, H.A.,Jiang, H.,Xu, Y.,Shen, J.
Pharmacokinetics-Driven Optimization of 4(3 H)-Pyrimidinones as Phosphodiesterase Type 5 Inhibitors Leading to TPN171, a Clinical Candidate for the Treatment of Pulmonary Arterial Hypertension.
J.Med.Chem., 62:4979-4990, 2019

PubMed Abstract: Phosphodiesterase type 5 (PDE5) inhibitors are first-line therapy for pulmonary arterial hypertension (PAH) and erectile dysfunction. As a continuing work to improve the terminal half-lives and oral bioavailabilities of our previously reported 4(3 H)-pyrimidones, a pharmacokinetics-driven optimization focusing on the terminal substituent is described. Two major congeneric series of 4(3 H)-pyrimidones, the aminosulfonylphenylpyrimidones and acylaminophenylpyrimidones, were designed, synthesized, and pharmacologically assessed in vitro and in vivo. Among them, compound 15 (TPN171) with subnanomolar potency for PDE5 and good selectivity over PDE6 was finally recognized as a potential drug candidate, and its pharmacokinetic profiles in rats and dogs are significantly improved compared to the starting compound (3). Moreover, TPN171 was proven to exert a longer lasting effect than sildenafil in animal models, providing a foundation for a once-daily oral administration for its clinical use. TPN171 is currently being investigated in a phase II clinical trial for the treatment of PAH.

PubMed: 31021628
DOI: 10.1021/acs.jmedchem.9b00123

Experimental method

X-RAY DIFFRACTION (2.155 Å)