Discovery and Structural Optimization of Toddacoumalone Derivatives as Novel PDE4 Inhibitors for the Topical Treatment of Psoriasis

Abstract

Psoriasis is a common immune-mediated skin disorder manifesting in abnormal skin plaques, and phosphodiesterase 4 (PDE4) is an effective target for the treatment of inflammatory diseases such as psoriasis. Toddacoumalone is a natural PDE4 inhibitor with moderate potency and imperfect drug-like properties. To discover novel and potent PDE4 inhibitors with considerable druggability, a series of toddacoumalone derivatives were designed and synthesized, leading to the compound (2R,4S)-6-ethyl-2-(2-hydroxyethyl)-2,8-dimethyl-4-(2-methylprop-1-en-1-yl)-2,3,4,6-tetrahydro-5H-pyrano­[3,2-c]­[1,8]­naphthyridin-5-one (33a) with high inhibitory potency (IC50 = 3.1 nM), satisfactory selectivity, favorable skin permeability, and a well-characterized binding mechanism. Encouragingly, topical administration of 33a exhibited remarkable therapeutic effects in an imiquimod-induced psoriasis mouse model.

Discovery of 4-Ethoxy-6-chloro-5-azaindazoles as Novel PDE4 Inhibitors for the Treatment of Alcohol Use Disorder and Alcoholic Liver Diseases

“…To maintain its binding mode in PDE4, we adopted another optimization strategy: cleavage of the tetrahydro-2 H -pyran-4-yl group to chain substituents encompassing a terminal hydrophilic group (Table ). In addition, it has been confirmed that introducing hydrophilic groups (such as OH and COOH) − into the end of the side chain is conducive to their binding to the metal region in the active cavity. In a manner akin to the ring-opening procedure of ZL6 , substitutions at N 1 or N 2 of 5-azaindazole were replaced by a length alkyl chain with 1–4 carbon atoms encompassing a terminal hydrophilic group, such as OH, COOH, and CONHOH.…”

Scouting Different Phosphodiesterase 4 Inhibitor Chemotypes in Silico To Guide the Design of Anti‐inflammatory/Antioxidant Agents

“…[20] The compound featured a naphthyridine scaffold and showed moderate potency as PDE4I, with the IC 50 value of 400 nM. The TCD2 bioactive conformation within the PDE4D catalytic site has been elucidated by X-ray crystallography (PDB code = 7W4X), [24] opening the possibility to proceed with the rational design of the further new analogues (see chemical structures in Supporting Information Table S3).…”

Identification of Dihydrobenzofuran Neolignans as Novel PDE4 Inhibitors and Evaluation of Antiatopic Dermatitis Efficacy in DNCB-Induced Mice Model

“…According to statistics by 2019, natural products as well as their derivatives accounted for 49.2% of the drugs approved by FDA, indicating that natural products are an invaluable source for the identification of lead compounds and pharmacophores . Many natural product derivatives were also discovered as effective PDE4 inhibitors. − In recent years, we have been engaged in the exploration of anti-inflammatory active ingredients from TCM, such as Magnolia biondii Pamp, Scrophularia ningpoensis Hemsl., Scrophularia dentata Royle ex Benth., Eriobotrya japonica (Thunb. )­Lindl., and so forth.…”