Design, synthesis, and biological evaluation of tetrahydroisoquinolines derivatives as novel, selective PDE4 inhibitors for antipsoriasis treatment.

In this study, a series of novel tetrahydroisoquinoline derivatives were developed based on the crystal structure of PDE4D in complex with compound 1. Anti-inflammatory effects of these compounds were evaluated, and compound 36, with high safety, permeability and selectivity, exhibited significant inhibitory potency against the enzymatic activity of PDE4D and the TNF-α release from the LPS-stimulated RAW 264.7 and hPBMCs. Moreover, an in vivo study demonstrated that a topical administration of 36 achieved more significant efficacy than calcipotriol to improve the features of psoriasis-like skin inflammation. Overall, our study provides a basis for further development of tetrahydroisoquinoline-based PDE4 inhibitors against psoriasis.
PMID: 33218684 [PubMed - as supplied by publisher]

Source: European Journal of Medicinal Chemistry - November 7, 2020 Category: Chemistry Authors: Zhang R, Li H, Zhang X, Li J, Su H, Lu Q, Dong G, Dou H, Fan C, Gu Z, Mu Q, Tang W, Xu Y, Liu H Tags: Eur J Med Chem Source Type: research