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PDBsum entry 4x48
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Membrane protein
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PDB id
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4x48
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References listed in PDB file
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Key reference
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Title
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The discovery and characterization of the α-Amino-3-Hydroxy-5-Methyl-4-Isoxazolepropionic acid (ampa) receptor potentiator n-{(3s,4s)-4-[4-(5-Cyano-2-Thienyl)phenoxy]tetrahydrofuran-3-Yl}propane-2-Sulfonamide (pf-04958242).
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Authors
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C.L.Shaffer,
N.C.Patel,
J.Schwarz,
R.J.Scialis,
Y.Wei,
X.J.Hou,
L.Xie,
K.Karki,
D.K.Bryce,
S.M.Osgood,
W.E.Hoffmann,
J.T.Lazzaro,
C.Chang,
D.F.Mcginnis,
S.M.Lotarski,
J.Liu,
R.S.Obach,
M.L.Weber,
L.Chen,
K.R.Zasadny,
P.A.Seymour,
C.J.Schmidt,
M.Hajós,
R.S.Hurst,
J.Pandit,
C.J.O'Donnell.
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Ref.
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J Med Chem, 2015,
58,
4291-4308.
[DOI no: ]
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PubMed id
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Abstract
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A unique tetrahydrofuran ether class of highly potent
α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor potentiators has
been identified using rational and structure-based drug design. An acyclic lead
compound, containing an ether-linked isopropylsulfonamide and biphenyl group,
was pharmacologically augmented by converting it to a conformationally
constrained tetrahydrofuran to improve key interactions with the human GluA2
ligand-binding domain. Subsequent replacement of the distal phenyl motif with
2-cyanothiophene to enhance its potency, selectivity, and metabolic stability
afforded
N-{(3S,4S)-4-[4-(5-cyano-2-thienyl)phenoxy]tetrahydrofuran-3-yl}propane-2-sulfonamide
(PF-04958242, 3), whose preclinical characterization suggests an adequate
therapeutic index, aided by low projected human oral pharmacokinetic
variability, for clinical studies exploring its ability to attenuate cognitive
deficits in patients with schizophrenia.
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