Structure-Aided Identification and Optimization of Tetrahydro-isoquinolines as Novel PDE4 Inhibitors Leading to Discovery of an Effective Antipsoriasis Agent

Abstract

Psoriasis is a common, chronic inflammatory disease characterized by abnormal skin plaques, and the effectiveness of phosphodiesterase 4 (PDE4) inhibitor to lessen the symptoms of psoriasis has been proved. Aiming to find a novel PDE4 inhibitor acting as an effective, safe, and convenient therapeutic agent, we constructed a library consisting of berberine analogues, and compound 2 with a tetrahydroisoquinoline scaffold was identified as a novel and potent hit. The structure-aided and cell-based structure–activity relationship studies on a series of tetrahydro-isoquinolines lead to efficient discovery of a qualified lead compound (16) with the high potency and selectivity, well-characterized binding mechanism, high cell permeability, good safety and pharmacokinetic profile, and impressive in vivo efficacy on antipsoriasis, in particular with a topical application. Thus, our study presents a prime example for efficient discovery of novel, potent lead compounds derived from natural products using a combination of medicinal chemistry, biochemical, biophysical, and pharmacological approaches.

DeepScreening: a deep learning-based screening web server for accelerating drug discovery

“…Recently, Zhang et al. (34) reported the discovery and optimization of Tetrahydro-isoquinolines as novel PDE4D inhibitors. The virtual screening hit compound 2 (IC 50 = 0.27 μM) and optimized lead compound 16 (IC 50 = 0.24 μM) were selected to test the application of DeepScreening.…”

Targeting PDE4 as a promising therapeutic strategy in chronic ulcerative colitis through modulating mucosal homeostasis

“…UC is one of the two major forms of inflammatory bowel diseases (IBD), which are closely linked with the precise interaction between gut microbiota, intestinal epithelial barrier function and mucosal immunity 15 . It has been demonstrated that targeting the cAMP-specific PDE4 displayed dramatic effects on suppression of cytokines in multiple inflammatory cells, including macrophages, NKT cells, neutrophils, and T helper cells, and intestinal epithelial cells 35 , 36 , 37 . In the past decades, though the PDE4 inhibitors, rolipram, tetomilast, and roflumilast have been investigated in experimental colitis, the adverse effects impeded the further clinical application 1 , 35 .…”

“…It has been demonstrated that targeting the cAMP-specific PDE4 displayed dramatic effects on suppression of cytokines in multiple inflammatory cells, including macrophages, NKT cells, neutrophils, and T helper cells, and intestinal epithelial cells 35 , 36 , 37 . In the past decades, though the PDE4 inhibitors, rolipram, tetomilast, and roflumilast have been investigated in experimental colitis, the adverse effects impeded the further clinical application 1 , 35 . By contrast, apremilast is a well-tolerated PDE4 inhibitor with little gastrointestinal side effects 38 .…”

Polyethylene Glycol Ointment Alleviates Psoriasis-Like Inflammation Through Down-Regulating the Function of Th17 Cells and MDSCs

“…In recent years, a growing number of studies have focused on the development of new drugs for psoriasis, including JAK inhibitors, Stat3 inhibitors, PDE4 inhibitors, TRK inhibitors, and AhR agonists (21)(22)(23)(24). However, there was no report yet on the treatment of PEG.…”