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PDBsum entry 5f1z
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Transferase/transferase inhibitor
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PDB id
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5f1z
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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-Based design and synthesis of 3-Amino-1,5-Dihydro-4h-Pyrazolopyridin-4-One derivatives as tyrosine kinase 2 inhibitors.
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Authors
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T.Yogo,
H.Nagamiya,
M.Seto,
S.Sasaki,
H.Shih-Chung,
Y.Ohba,
N.Tokunaga,
G.N.Lee,
C.Y.Rhim,
C.H.Yoon,
S.Y.Cho,
R.Skene,
S.Yamamoto,
Y.Satou,
M.Kuno,
T.Miyazaki,
H.Nakagawa,
A.Okabe,
S.Marui,
K.Aso,
M.Yoshida.
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Ref.
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J Med Chem, 2016,
59,
733-749.
[DOI no: ]
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PubMed id
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Abstract
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We report herein the discovery and optimization of
3-amino-1,5-dihydro-4H-pyrazolopyridin-4-one TYK2 inhibitors. High-throughput
screening against TYK2 and JAK1-3 provided aminoindazole derivative 1 as a hit
compound. Scaffold hopping of the aminoindazole core led to the discovery of
3-amino-1,5-dihydro-4H-pyrazolopyridin-4-one derivative 3 as a novel chemotype
of TYK2 inhibitors. Interestingly, initial SAR study suggested that this
scaffold could have a vertically flipped binding mode, which prompted us to
introduce a substituent at the 7-position as a moiety directed toward the
solvent-exposed region. Introduction of a 1-methyl-3-pyrazolyl moiety at the
7-position resulted in a dramatic increase in TYK2 inhibitory activity, and
further optimization led to the discovery of 20. Compound 20 inhibited
IL-23-induced IL-22 production in a rat PD assay, as well as inhibited IL-23
signaling in human PBMC. Furthermore, 20 showed selectivity for IL-23 signaling
inhibition against GM-CSF, demonstrating the unique cytokine selectivity of the
novel TYK2 inhibitor.
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