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PDBsum entry 6imr
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Hydrolase/hydrolase inhibitor
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PDB id
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6imr
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References listed in PDB file
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Key reference
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Title
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Structure-Aided identification and optimization of tetrahydro-Isoquinolines as novel pde4 inhibitors leading to discovery of an effective antipsoriasis agent.
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Authors
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X.Zhang,
G.Dong,
H.Li,
W.Chen,
J.Li,
C.Feng,
Z.Gu,
F.Zhu,
R.Zhang,
M.Li,
W.Tang,
H.Liu,
Y.Xu.
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Ref.
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J Med Chem, 2019,
62,
5579-5593.
[DOI no: ]
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PubMed id
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Abstract
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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.
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