Details of the Drug Therapeutic Target (DTT)

General Information of Drug Therapeutic Target (DTT) (ID: TT7QNVC)

• DTT Name: Glucose-dependent insulinotropic receptor (GPR119)
• Synonyms: GPR119; G-protein coupled receptor 119
• Gene Name: GPR119
• DTT Type: Successful target; [1]
• BioChemical Class: GPCR rhodopsin
• UniProt ID: GP119_HUMAN
• TTD ID: T93788
• Sequence:
  MESSFSFGVILAVLASLIIATNTLVAVAVLLLIHKNDGVSLCFTLNLAVADTLIGVAISG
  LLTDQLSSPSRPTQKTLCSLRMAFVTSSAAASVLTVMLITFDRYLAIKQPFRYLKIMSGF
  VAGACIAGLWLVSYLIGFLPLGIPMFQQTAYKGQCSFFAVFHPHFVLTLSCVGFFPAMLL
  FVFFYCDMLKIASMHSQQIRKMEHAGAMAGGYRSPRTPSDFKALRTVSVLIGSFALSWTP
  FLITGIVQVACQECHLYLVLERYLWLLGVGNSLLNPLIYAYWQKEVRLQLYHMALGVKKV
  LTSFLLFLSARNCGPERPRESSCHIVTISSSEFDG
• Function: Receptor for the endogenous fatty-acid ethanolamide oleoylethanolamide (OEA) and lysophosphatidylcholine (LPC). Functions as a glucose-dependent insulinotropic receptor. The activity of this receptor is mediated by G proteins which activate adenylate cyclase. Seems to act through a G(s) mediated pathway.
• KEGG Pathway:
  cAMP signaling pathway (hsa04024)
  Insulin secretion (hsa04911)
• Reactome Pathway:
  Synthesis, secretion, and inactivation of Glucose-dependent Insulinotropic Polypeptide (GIP) (R-HSA-400511)
  Synthesis, secretion, and inactivation of Glucagon-like Peptide-1 (GLP-1) (R-HSA-381771)

Molecular Interaction Atlas (MIA) of This DTT

1 Approved Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
Guanfacine extended release	DMB1CZ8	Attention deficit hyperactivity disorder	6A05.Z	Approved	[1]

6 Clinical Trial Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
DS-8500	DMUXIRM	Diabetic complication	5A2Y	Phase 2	[2]
GSK1292263	DMDMXKQ	Gastric adenocarcinoma	2B72	Phase 2	[3]
SAR-260093	DMBJU2G	Type-2 diabetes	5A11	Phase 2	[4]
APD-597	DM36FOG	Type-2 diabetes	5A11	Phase 1	[5]
BMS-903452	DM7JW0B	Type-2 diabetes	5A11	Phase 1	[6]
DA-1241	DMPJA64	Type 2 diabetes	5A11	Phase 1	[7]

2 Discontinued Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
APD668	DMN8R2U	Type-2 diabetes	5A11	Discontinued in Phase 1	[8]
PSN821	DMGEWUS	Type-2 diabetes	5A11	Terminated	[9]

33 Investigative Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
(R)-N-oleoyltyrosinol	DMIHR14	Discovery agent	N.A.	Investigative	[10]
(S)-N-oleoyltyrosinol	DMNOWZ2	Discovery agent	N.A.	Investigative	[10]
1-oleoyl glycerol	DM5KU8S	Discovery agent	N.A.	Investigative	[11]
1-palmitoyl-lysophosphatidylcholine	DM9ZK0M	Discovery agent	N.A.	Investigative	[12]
1-stearoyl-lysophosphatidylcholine	DM7K0B3	Discovery agent	N.A.	Investigative	[12]
2-oleoyl glycerol	DM5PXQU	Discovery agent	N.A.	Investigative	[11]
AR-7947	DM34P90	Non-insulin dependent diabetes	5A11	Investigative	[1]
AR231453	DMN8W46	Discovery agent	N.A.	Investigative	[13]
AS-1907417	DM0MAIW	Non-insulin dependent diabetes	5A11	Investigative	[1]
AS1269574	DM170G5	Discovery agent	N.A.	Investigative	[14]
LC34AD3	DMGWSCI	Non-insulin dependent diabetes	5A11	Investigative	[1]
lysophosphatidylethanolamine	DMI4FKH	Discovery agent	N.A.	Investigative	[12]
lysophosphatidylinositol	DMETM3R	Discovery agent	N.A.	Investigative	[12]
MBX-3254	DM89WA1	Non-insulin dependent diabetes	5A11	Investigative	[1]
N-oleoylethanolamide	DMJQ4L7	Discovery agent	N.A.	Investigative	[15]
oleoyl-lysophosphatidylcholine	DMB5KQ4	Discovery agent	N.A.	Investigative	[12]
PMID21273063C1	DMEFUZW	Discovery agent	N.A.	Investigative	[16]
PMID21273063C36	DMFYJ6O	Discovery agent	N.A.	Investigative	[16]
PMID21273063C58	DMDCUYB	Discovery agent	N.A.	Investigative	[16]
PMID21310611C3	DMTOM3E	Discovery agent	N.A.	Investigative	[17]
PMID21444206C23	DM9YVPU	Discovery agent	N.A.	Investigative	[18]
PMID21444206C3a	DMN50B9	Discovery agent	N.A.	Investigative	[18]
PMID21444206C3j	DMM1YBE	Discovery agent	N.A.	Investigative	[18]
PMID21444206C8g	DMR21YD	Discovery agent	N.A.	Investigative	[18]
PMID21536438C20f	DMHWX2O	Discovery agent	N.A.	Investigative	[19]
PMID21536438C36j	DM06V1Q	Discovery agent	N.A.	Investigative	[19]
PMID21939274C1	DMEUQFG	Discovery agent	N.A.	Investigative	[20]
PMID21939274C2	DMRCAEI	Discovery agent	N.A.	Investigative	[20]
PMID22545772C42	DMVZQ6U	Discovery agent	N.A.	Investigative	[21]
PSN375963	DM2U9SR	Discovery agent	N.A.	Investigative	[22]
PSN632408	DMJIB8N	Discovery agent	N.A.	Investigative	[22]
RO-5212651	DMP0GA6	Non-insulin dependent diabetes	5A11	Investigative	[1]
SEA	DMSB4WO	Discovery agent	N.A.	Investigative	[1]

References

• [1] URL: http://www.guidetopharmacology.org Nucleic Acids Res. 2015 Oct 12. pii: gkv1037. The IUPHAR/BPS Guide to PHARMACOLOGY in 2016: towards curated quantitative interactions between 1300 protein targets and 6000 ligands. (Target id: 126).
• [2] Addressing Unmet Medical Needs in Type 2 Diabetes: A Narrative Review of Drugs under Development. Curr Diabetes Rev. 2015 March; 11(1): 17-31.
• [3] Gut hormone pharmacology of a novel GPR119 agonist (GSK1292263), metformin, and sitagliptin in type 2 diabetes mellitus: results from two randomized studies.PLoS One.2014 Apr 3;9(4):e92494.
• [4] GPR119 agonists for the treatment of type 2 diabetes. Expert Opin Ther Pat. 2009 Oct;19(10):1339-59.
• [5] Discovery of a second generation agonist of the orphan G-protein coupled receptor GPR119 with an improved profile. Bioorg Med Chem Lett. 2012 Feb 15;22(4):1750-5.
• [6] Discovery of 5-chloro-4-((1-(5-chloropyrimidin-2-yl)piperidin-4-yl)oxy)-1-(2-fluoro-4-(methylsulfonyl)phenyl)pyridin-2(1H)-one (BMS-903452), an antidiabetic clinical candidate targeting GPR119. J MedChem. 2014 Sep 25;57(18):7499-508.
• [7] ClinicalTrials.gov (NCT03646721) A Study to Evaluate the Safety, Tolerability, PK and PD of DA-1241 in Healthy Male Subjects and Subjects With T2DM. U.S. National Institutes of Health.
• [8] Announces Initiation of Phase 1 Clinical Trial of Arena Type 2 Diabetes Drug Candidate in Collaboration With Ortho-McNeil. Arena Pharmaceuticals, Inc. FEBRUARY 07, 2006.
• [9] Clinical pipeline report, company report or official report of Astellas Pharma (2011).
• [10] N-oleoyldopamine enhances glucose homeostasis through the activation of GPR119. Mol Endocrinol. 2010 Jan;24(1):161-70.
• [11] 2-Oleoyl glycerol is a GPR119 agonist and signals GLP-1 release in humans. J Clin Endocrinol Metab. 2011 Sep;96(9):E1409-17.
• [12] Lysophosphatidylcholine enhances glucose-dependent insulin secretion via an orphan G-protein-coupled receptor. Biochem Biophys Res Commun. 2005 Jan 28;326(4):744-51.
• [13] A role for beta-cell-expressed G protein-coupled receptor 119 in glycemic control by enhancing glucose-dependent insulin release. Endocrinology. 2007 Jun;148(6):2601-9.
• [14] Identification of a novel GPR119 agonist, AS1269574, with in vitro and in vivo glucose-stimulated insulin secretion. Biochem Biophys Res Commun. 2010 Sep 24;400(3):437-41.
• [15] Screening beta-arrestin recruitment for the identification of natural ligands for orphan G-protein-coupled receptors. J Biomol Screen. 2013 Jun;18(5):599-609.
• [16] Design of potent and selective GPR119 agonists for type II diabetes. Bioorg Med Chem Lett. 2011 May 1;21(9):2665-9.
• [17] Design and evaluation of a 2-(2,3,6-trifluorophenyl)acetamide derivative as an agonist of the GPR119 receptor. Bioorg Med Chem Lett. 2011 Mar 1;21(5):1306-9.
• [18] Discovery of fused bicyclic agonists of the orphan G-protein coupled receptor GPR119 with in vivo activity in rodent models of glucose control. Bioorg Med Chem Lett. 2011 May 15;21(10):3134-41.
• [19] Discovery of a nortropanol derivative as a potent and orally active GPR119 agonist for type 2 diabetes. Bioorg Med Chem Lett. 2011 Jun 1;21(11):3290-6.
• [20] Oxidative metabolism of a quinoxaline derivative by xanthine oxidase in rodent plasma. Chem Res Toxicol. 2011 Dec 19;24(12):2207-16.
• [21] Use of small-molecule crystal structures to address solubility in a novel series of G protein coupled receptor 119 agonists: optimization of a lead and in vivo evaluation. J Med Chem. 2012 Jun 14;55(11):5361-79.
• [22] Deorphanization of a G protein-coupled receptor for oleoylethanolamide and its use in the discovery of small-molecule hypophagic agents. Cell Metab. 2006 Mar;3(3):167-75.