Validation of Phosphodiesterase-10 as a Novel Target for Pulmonary Arterial Hypertension via Highly Selective and Subnanomolar Inhibitors
Validation of Phosphodiesterase-10 as a Novel Target for Pulmonary Arterial Hypertension via Highly Selective and Subnanomolar Inhibitors
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通过高选择性和亚纳摩尔抑制剂验证磷酸二酯酶 10 作为肺动脉高压的新靶点
DOI：
10.1021/acs.jmedchem.9b00224
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发表时间：
2019-04-11
影响因子：
7.3
通讯作者：
Luo, Hai-Bin
中科院分区：
文献类型：
--
作者：
Huang, Yi-You;Yu, Yan-Fa;Luo, Hai-Bin
肺动脉高压（PAH）导致肺血管阻力病理性增加，导致右心衰竭并最终死亡。以前，磷酸二酯酶-10（PDE 10）被报道是PAH的一个有前途的目标，基于非选择性PDE抑制剂罂粟碱的研究，但几乎没有进展，以确认PDE 10抑制剂的实际应用。为了验证PAH是否通过PDE 10抑制而不是其他PDE亚型改善，在这里，我们报告了一种综合策略，以发现高选择性PDE 10抑制剂作为化学探针。结构优化导致PDE 10抑制剂2b具有亚纳摩尔亲和力和对其他PDE> 45000倍的良好选择性。PDE 10 -2b复合物的共晶结构揭示了2b和Tyr 693之间重要的氢键相互作用。最后，化合物2b显著降低PAH大鼠的动脉压，从而验证了PDE 10作为新的抗PAH靶点的潜力。这些结果表明，PDE 10抑制可能是PAH的一种可行治疗选择。
Pulmonary arterial hypertension (PAH) causes pathological increase in pulmonary vascular resistance, leading to right-heart failure and eventual death. Previously, phosphodiesterase-10 (PDE10) was reported to be a promising target for PAH based on the studies with a nonselective PDE inhibitor papaverine, but little progress has been made to confirm the practical application of PDE10 inhibitors. To validate whether PAH is ameliorated by PDE10 inhibition rather than other PDE isoforms, here we report an integrated strategy to discover highly selective PDE10 inhibitors as chemical probes. Structural optimization resulted in a PDE10 inhibitor 2b with subnanomolar affinity and good selectivity of >45 000-fold against other PDEs. The cocrystal structure of the PDE10-2b complex revealed an important H-bond interaction between 2b and Tyr693. Finally, compound 2b significantly decreased the arterial pressure in PAH rats and thus validated the potential of PDE10 as a novel anti-PAH target. These findings suggest that PDE10 inhibition may be a viable treatment option for PAH.