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PDBsum entry 4mvh
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Hydrolase/hydrolase inhibitor
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PDB id
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4mvh
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References listed in PDB file
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Key reference
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Title
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Design, Optimization, And biological evaluation of novel keto-Benzimidazoles as potent and selective inhibitors of phosphodiesterase 10a (pde10a).
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Authors
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E.Hu,
R.K.Kunz,
N.Chen,
S.Rumfelt,
A.Siegmund,
K.Andrews,
S.Chmait,
S.Zhao,
C.Davis,
H.Chen,
D.Lester-Zeiner,
J.Ma,
C.Biorn,
J.Shi,
A.Porter,
J.Treanor,
J.R.Allen.
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Ref.
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J Med Chem, 2013,
56,
8781-8792.
[DOI no: ]
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PubMed id
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Abstract
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Our development of PDE10A inhibitors began with an HTS screening hit (1) that
exhibited both high p-glycoprotein (P-gp) efflux ratios in rat and human and
poor metabolic stability. On the basis of cocrystal structure of 1 in human
PDE10A enzyme, we designed a novel keto-benzimidazole 26 with comparable PDE10A
potency devoid of efflux liabilities. On target in vivo coverage of PDE10A in
rat brain was assessed using our previously reported LC-MS/MS receptor occupancy
(RO) technology. Compound 26 achieved 55% RO of PDE10A at 30 mg/kg po and
covered PDE10A receptors in rat brain in a dose-dependent manner. Cocrystal
structure of 26 in PDE10A confirmed the binding mode of the novel scaffold.
Further optimization resulted in the identification of keto-benzimidazole 34,
which showed an increased in vivo efficacy of 57% RO in rats at 10 mg/kg po and
an improved in vivo rat clearance and oral bioavailability.
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