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PDBsum entry 6tpd
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References listed in PDB file
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Key reference
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Title
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Fragment-Based discovery of pyrazolopyridones as jak1 inhibitors with excellent subtype selectivity.
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Authors
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B.B.Hansen,
T.H.Jepsen,
M.Larsen,
R.Sindet,
T.Vifian,
M.N.Burhardt,
J.Larsen,
J.G.Seitzberg,
M.A.Carnerup,
A.Jerre,
C.Mølck,
P.Lovato,
S.Rai,
V.R.Nasipireddy,
A.Ritzén.
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Ref.
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J Med Chem, 2020,
63,
7008-7032.
[DOI no: ]
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PubMed id
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Abstract
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Herein, we report the discovery of a series of JAK1-selective kinase inhibitors
with high potency and excellent JAK family subtype selectivity. A fragment
screening hit 1 with a pyrazolopyridone core and a JAK1 bias was selected
as the starting point for our fragment-based lead generation efforts. A
two-stage strategy was chosen with the dual aims of improving potency and JAK1
selectivity: Optimization of the lipophilic ribose pocket-targeting substituent
was followed by the introduction of a variety of P-loop-targeting functional
groups. Combining the best moieties from both stages of the optimization
afforded compound 40, which showed excellent potency and selectivity.
Metabolism studies in vitro and in vivo together with an in
vitro safety evaluation suggest that 40 may be a viable lead compound
for the development of highly subtype-selective JAK1 inhibitors.
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