- Structure-based discovery of highly selective phosphodiesterase-9A inhibitors and implications for inhibitor design
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A new series of phosphodiesterase-9 (PDE9) inhibitors that contain a scaffold of 6-amino-pyrazolopyrimidinone have been discovered by a combination of structure-based design and computational docking. This procedure significantly saved the load of chemical synthesis and is an effective method for the discovery of inhibitors. The best compound 28 has an IC50 of 21 nM and 3.3 μM, respectively, for PDE9 and PDE5 and about 3 orders of magnitude of selectivity against other PDE families. The crystal structure of the PDE9 catalytic domain in complex with 28 has been determined and shows a hydrogen bond between 28 and Tyr424. This hydrogen bond may account for the 860-fold selectivity of 28 against PDE1B, in comparison with about 30-fold selectivity of BAY73-6691. Thus, our studies suggest that Tyr424, a unique residue of PDE8 and PDE9, is a potential target for improvement of selectivity of PDE9 inhibitors.
- Meng, Fei,Huang, Manna,Zhu, Xinhai,Wan, Yiqian,Hou, Jing,Shao, Yong-Xian,Cai, Yonghong,Li, Zhe,Xu, Jie,Liu, Peiqing,Luo, Hai-Bin,Ke, Hengming,Wu, Pei-Ying
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p. 8549 - 8558,10
(2020/09/15)
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- Pyrazolo-pyrimidines: A novel heterocyclic scaffold for potent and selective p38α inhibitors
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The synthesis and structure-activity relationships (SAR) of p38α MAP kinase inhibitors based on a pyrazolo-pyrimidine scaffold are described. These studies led to the identification of compound 2x as a potent and selective inhibitor of p38α MAP kinase with excellent cellular potency toward the inhibition of TNFα production. Compound 2x was highly efficacious in vivo in inhibiting TNFα production in an acute murine model of TNFα production. X-ray co-crystallography of a pyrazolo-pyrimidine analog 2b bound to unphosphorylated p38α is also disclosed.
- Das, Jagabandhu,Moquin, Robert V.,Pitt, Sidney,Zhang, Rosemary,Shen, Ding Ren,McIntyre, Kim W.,Gillooly, Kathleen,Doweyko, Arthur M.,Sack, John S.,Zhang, Hongjian,Kiefer, Susan E.,Kish, Kevin,McKinnon, Murray,Barrish, Joel C.,Dodd, John H.,Schieven, Gary L.,Leftheris, Katerina
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p. 2652 - 2657
(2008/12/21)
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