ABSTRACT
This Letter describes the discovery of a series of potent inhibitors of Human Uric Acid Transporter 1 (hURAT1). Lead generation and optimization via 3D pharmacophore analysis resulted in compound 41. With an IC50 of 33.7nM, 41 also demonstrated good oral bioavailability in rat (74.8%) and displayed a consistent PK profile across all species tested (rat, dog and monkey).
Subject(s)
Cyclobutanes/pharmacology , Gout Suppressants/pharmacology , Organic Anion Transporters/antagonists & inhibitors , Organic Cation Transport Proteins/antagonists & inhibitors , Quinolines/pharmacology , Animals , Cyclobutanes/chemical synthesis , Cyclobutanes/pharmacokinetics , Dogs , Gout Suppressants/chemical synthesis , Gout Suppressants/pharmacokinetics , Humans , Macaca fascicularis , Microsomes, Liver/metabolism , Molecular Docking Simulation , Organic Anion Transporters/chemistry , Organic Cation Transport Proteins/chemistry , Quinolines/chemical synthesis , Quinolines/pharmacokinetics , Rats , Rats, Sprague-Dawley , Structural Homology, Protein , Structure-Activity RelationshipABSTRACT
In the mol-ecule of the title compound, C(11)H(14)N(2)O(4), a bifurcated intra/intermolecular N-Hâ¯(O,O) hydrogen bond occurs.The intramolecular component results in a non-planar six-membered ring with a flattened-boat conformation. In the crystal structure, the inter-molecular interaction links the mol-ecules into chains parallel to the b axis.
ABSTRACT
In the title compound, C(9)H(10)N(2)O(4)S, which is an important inter-mediate for the preparation of anti-tumor platinum drugs, the dioxolane ring adopts an envelope conformation with the C atom bonded to the thienyl ring at the flap position. Intra-molecular N-Hâ¯O and C-Hâ¯O hydrogen bonds result in the formation of two five-membered rings having envelope conformations. In the crystal structure, inter-molecular N-Hâ¯O and C-Hâ¯O hydrogen bonds link the mol-ecules into a three-dimensional network.
ABSTRACT
In the mol-ecule of the title compound, C(12)H(16)N(2)O(4), an intra-molecular N-Hâ¯O hydrogen bond results in the formation of a six-membered ring having an envelope conformation. In the crystal structure, a bifurcated intra/intermolecular N-Hâ¯(O,O) hydrogen bond generates inversion dimers.
ABSTRACT
In the mol-ecule of the title compound, C(14)H(12)N(2)O(4), the aromatic rings are oriented at a dihedral angle of 51.50â (4)°. An intra-molecular N-Hâ¯O inter-action results in the formation of a six-membered ring having an envelope conformation. In the crystal structure, inter-molecular N-Hâ¯O inter-actions link the mol-ecules into centrosymmetric dimers. π-π contacts between the benzene rings [centroid-centroid distance = 3.708â (1)â Å] may further stabilize the structure.
ABSTRACT
In the mol-ecule of the title compound, C(11)H(11)FN(2)O(4), the five-membered ring adopts an envelope conformation. An intra-molecular N-Hâ¯F hydrogen bond occurs. In the crystal structure, inter-molecular N-Hâ¯O hydrogen bonds link the mol-ecules.
ABSTRACT
In the title compound, C(8)H(6)ClNO(4), the mol-ecules are linked by C-Hâ¯O inter-actions to form a chain parallel to the a axis. The chains are further connected by slipped π-π stacking between symmetry-related benzene rings, with a centroid-to-centroid distance of 3.646â (2)â Å and an inter-planar distance of 3.474â Å, resulting in an offset of 1.106â Å.
ABSTRACT
In the mol-ecule of the title compound, C(9)H(8)ClNO(4), an intra-molecular C-Hâ¯O hydrogen bond results in the formation of a planar five-membered ring, which is nearly coplanar with the adjacent six-membered ring, the rings being oriented at a dihedral angle of 4.40â (3)°. In the crystal structure, inter-molecular C-Hâ¯O hydrogen bonds link the mol-ecules.
ABSTRACT
In the title compound C(21)H(21)P, the P atom is situated on a crystallographic threefold rotatory-inversion axis, resulting in threefold rotation symmetry of the title compound. The dihedral angles between the symmetry-related benzene rings are 87.40â (18)°.
ABSTRACT
In the mol-ecule of the title compound, C(6)H(6)BrNO, the methyl C and oxide O atoms lie in the pyridine ring plane, while the Br atom is displaced by 0.103â (3)â Å. In the crystal structure, inter-molecular C-Hâ¯O hydrogen bonds link the mol-ecules into centrosymmetric dimers.
ABSTRACT
In the crystal of the title compound, C(7)H(5)ClN(2)O(3), the molecules are linked by N-Hâ¯O and C-Hâ¯O hydrogen bonds. The π-π contact between the benzene rings, [centroid-centroid distance = 3.803â (3)â Å] may further stabilize the structure.
ABSTRACT
In the title compound, C(15)H(14)N(2)O(4), the aromatic rings are oriented at a dihedral angle of 78.33â (3)°. An intra-molecular N-Hâ¯O hydrogen bond results in a non-planar six-membered ring with a flattened-boat conformation. In the crystal structure, inter-molecular N-Hâ¯O hydrogen bonds link the mol-ecules. π-π contacts between the phenyl rings and both the phenyl and benzene rings, [centroid-centroid distances = 3.841â (3) and 3.961â (3)â Å] may further stabilize the structure.
ABSTRACT
In the title compound, C(7)H(3)ClN(2)O(2), the Cl, C and N atoms are coplanar with the aromatic ring. In the crystal structure, weak inter-molecular C-Hâ¯O and C-Hâ¯N hydrogen bonds link the mol-ecules. The π-π contact between the benzene rings, [centroid-centroid distances = 3.912â (3)â Å] may further stabilize the structure.