TY - JOUR
AU - Xu, Yechun
AB - 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.
TI - Structure-Aided Identification and Optimization of Tetrahydro-isoquinolines as Novel PDE4 Inhibitors Leading to Discovery of an Effective Antipsoriasis Agent.
JF - Journal of Medicinal Chemistry
DO - 10.1021/acs.jmedchem.9b00518
DA - 2020-06-15
UR - https://www.deepdyve.com/lp/pubmed/structure-aided-identification-and-optimization-of-tetrahydro-MaAUa6mHxf
SP - 5579
EP - 5593
VL - 62
IS - 11
DP - DeepDyve
ER -