4-amino-5-chloro-N-[(3R-4S)-1-[3-(4-fluorophenoxy)propyl]-3-methoxy-4-piperidinyl]-2-methoxybenzamide and Psoriasis

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.

Topics: Animals; Caco-2 Cells; Catalytic Domain; Cyclic Nucleotide Phosphodiesterases, Type 4; Drug Design; Drug Evaluation, Preclinical; Female; HEK293 Cells; Humans; Male; Mice; Models, Molecular; Phosphodiesterase 4 Inhibitors; Psoriasis; Rats; Stereoisomerism; Structure-Activity Relationship; Tetrahydroisoquinolines; Tissue Distribution