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Development of Highly Potent Phosphodiesterase 4 Inhibitors With Anti-Neuroinflammation Potential: Design, Synthesis, and Structure-Activity Relationship Study of Catecholamides Bearing Aromatic Rings

Development of Highly Potent Phosphodiesterase 4 Inhibitors With Anti-Neuroinflammation Potential: Design, Synthesis, and Structure-Activity Relationship Study of Catecholamides Bearing Aromatic Rings

Zhong-Zhen Zhou, Bing-Chen Ge, Qiu-Ping Zhong, Chang Huang, Yu-Fang Cheng, Xue-Mei Yang, Hai-Tao Wang, Jiang-Ping Xu

Eur J Med Chem. 2016 Nov 29;124:372-379.

PMID: 27597413

Abstract:

In this study, catecholamides (7a-l) bearing different aromatic rings (such as pyridine-2-yl, pyridine-3-yl, phenyl, and 2-chlorophenyl groups) were synthesized as potent phosphodiesterase (PDE) 4 inhibitors. The inhibitory activities of these compounds were evaluated against the core catalytic domains of human PDE4 (PDE4CAT), full-length PDE4A4, PDE4B1, PDE4C1, and PDE4D7 enzymes, and other PDE family members. Eight of the synthesized compounds were identified as having submicromolar IC50 values in the mid-to low-nanomolar range. Careful analysis on the structure-activity relationship of compounds 7a-l revealed that the replacement of the 4-methoxy group with the difluoromethoxy group improved inhibitory activities. More interesting, 4-difluoromethoxybenzamides 7i and 7j exhibited preference for PDE4 with higher selectivities of about 3333 and 1111-fold over other PDEs, respectively. In addition, compound 7j with wonderful PDE4D7 inhibitory activities inhibited LPS-induced TNF-α production in microglia.

Chemicals Related in the Paper:

Catalog Number	Product Name	Structure	CAS Number	Price
IAR4245704	PDE4C1 Active human			Price

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