Human G Protein-Coupled Receptor and Modulators Thereof for the Treatment of Hyperglycemia and Related Disorders

A method of identifying one or more candidate compounds as a modulator of glucose uptake in adipocytes or skeletal muscle cells in a mammal or as a modulator of blood glucose concentration in a mammal, said method comprising the steps of:

• (a) contacting the one or more candidate compounds with a RUP43 GPCR, wherein the receptor couples to a G protein, said receptor comprising a GPR131 amino acid sequence selected from the group consisting of:
• (i) the amino acid sequence of SEQ ID NO:2;
• (ii) amino acids 2-330 of SEQ ID NO:2;
• (iii) amino acids 2-330 of SEQ ID NO:2, with the proviso that the RUP43 G protein-coupled receptor does not comprise the methionine residue at amino acid position 1 of SEQ ID NO:2;
• (iv) the amino acid sequence of (i), (ii) or (iii) wherein the alanine at amino acid position 223 of SEQ ID NO:2 is substituted with lysine;
• (v) the amino acid sequence of a G protein-coupled receptor encoded by a polynucleotide that is amplifiable by polymerase chain reaction (PCR) on a human DNA sample using primers SEQ ID NO:3 and SEQ ID NO:4;
• (vi) the amino acid sequence of SEQ ID NO:6;
• (vii) the amino acid sequence of a G protein-coupled receptor having an amino acid sequence derived from SEQ ID NO:2 by substitution, deletion or addition of one or several amino acids in the amino acid sequence of SEQ ID NO:2;
• (viii) the amino acid sequence of a G protein-coupled receptor encoded by a polynucleotide that hybridizes under stringent conditions to the complement of SEQ ID NO:
• 1;
• (ix) the amino acid sequence of a G protein-coupled receptor having an amino acid sequence having at least 75% identity to SEQ ID NO:2;
• and
• (x) the amino acid sequence of an allele or mammalian ortholog of human RUP43 GPCR having the amino acid sequence of SEQ ID NO:2;
• and
• (b) determining whether the receptor functionality is inhibited or stimulated;
• wherein inhibition or stimulation of said receptor functionality is indicative of the candidate compound being a modulator of glucose uptake in adipocytes or skeletal muscle cells in a mammal or a modulator of blood glucose concentration in the blood of a mammal.

A compound of Formula (II):

• or a pharmaceutically acceptable salt thereof,
• wherein:
• R1 is H or C1-6 alkyl;
• R2 is a 2-methyl-4,5,6,7-tetrahydro-2H-indazol-3-yl group;
• or
• R1 and R2 together with the nitrogen to which they are bonded form a 3,4-dihydro-2H-quinoline-1-yl group;
• and
• R10 and R11 are each independently H or halogen.

A method of preventing or treating a metabolic disorder comprising providing or administering to a mammal in need of said prevention or treatment a therapeutically effective amount of an agonist of the mammalian RUP43 GPCR or a pharmaceutical composition comprising the agonist and a pharmaceutically acceptable carrier, wherein the metabolic disorder is selected from the group consisting of:

• (a) diabetes;
• (b) impaired glucose tolerance;
• (c) insulin resistance;
• and
• (d) hyperinsulinemia.

A method of preventing or treating a complication of an elevated blood glucose concentration comprising providing or administering to a mammal in need of said prevention or treatment a therapeutically effective amount of an agonist of the mammalian RUP43 GPCR or a pharmaceutical composition comprising the agonist and a pharmaceutically acceptable carrier, wherein said complication is selected from the group consisting of:

• (a) Syndrome X;
• (b) atherosclerosis;
• (c) atheromatous disease;
• (d) heart disease;
• (e) hypertension;
• (f) stroke;
• (g) neuropathy;
• (h) retinopathy;
• (i) nephropathy;
• and
• j) peripheral vascular disease.

A method of identifying one or more candidate compounds as a compound that binds to a RUP43 GPCR, said receptor comprising a GPR131 amino acid sequence selected from the group consisting of:

• (a) the amino acid sequence of SEQ ID NO:2;
• (b) amino acids 2-330 of SEQ ID NO:2;
• (c) amino acids 2-330 of SEQ ID NO:2, with the proviso that the RUP43 G protein-coupled receptor does not comprise the methionine residue at amino acid position 1 of SEQ ID NO:2;
• (d) the amino acid sequence of (a), (b) or (c) wherein the alanine at amino acid position 223 of SEQ ID NO:2 is substituted with lysine;
• (e) the amino acid sequence of a G protein-coupled receptor encoded by a polynucleotide that is amplifiable by polymerase chain reaction (PCR) on a human DNA sample using primers SEQ ID NO:3 and SEQ ID NO:4;
• (f) the amino acid sequence of SEQ ID NO:6;
• (g) the amino acid sequence of a G protein-coupled receptor having an amino acid sequence derived from SEQ ID NO:2 by substitution, deletion or addition of one or several amino acids in the amino acid sequence of SEQ ID NO:2;
• (h) the amino acid sequence of a G protein-coupled receptor encoded by a polynucleotide that hybridizes under stringent conditions to the complement of SEQ ID NO:
• 1;
• (i) the amino acid sequence of a G protein-coupled receptor having an amino acid sequence having at least 75% identity to SEQ ID NO:2;
• and
• (j) the amino acid sequence of an allele or mammalian ortholog of human RUP43 GPCR having the amino acid sequence of SEQ ID NO:2;
• comprising the steps of:
• (a′) contacting the receptor with a detectably labeled known ligand of the receptor in the presence or absence of the candidate compound;
• and
• (b′) determining whether the binding of said labeled known ligand to the receptor is inhibited in the presence of the candidate compound;
• wherein said inhibition is indicative of the candidate compound being a compound that binds to the RUP43 GPCR.