Details of the Drug Therapeutic Target (DTT)

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

• DTT Name: Oxytocin receptor (OTR)
• Synonyms: OT-R
• Gene Name: OXTR
• DTT Type: Successful target; [1]
• Related Disease:
  Acute diabete complication [ICD-11: 5A2Y]
  Autism spectrum disorder [ICD-11: 6A02]
  Postpartum haemorrhage [ICD-11: JA43]
• BioChemical Class: GPCR rhodopsin
• UniProt ID: OXYR_HUMAN
• TTD ID: T84486
• Sequence:
  MEGALAANWSAEAANASAAPPGAEGNRTAGPPRRNEALARVEVAVLCLILLLALSGNACV
  LLALRTTRQKHSRLFFFMKHLSIADLVVAVFQVLPQLLWDITFRFYGPDLLCRLVKYLQV
  VGMFASTYLLLLMSLDRCLAICQPLRSLRRRTDRLAVLATWLGCLVASAPQVHIFSLREV
  ADGVFDCWAVFIQPWGPKAYITWITLAVYIVPVIVLAACYGLISFKIWQNLRLKTAAAAA
  AEAPEGAAAGDGGRVALARVSSVKLISKAKIRTVKMTFIIVLAFIVCWTPFFFVQMWSVW
  DANAPKEASAFIIVMLLASLNSCCNPWIYMLFTGHLFHELVQRFLCCSASYLKGRRLGET
  SASKKSNSSSFVLSHRSSSQRSCSQPSTA
• Function: The activity of this receptor is mediated by G proteins which activate a phosphatidylinositol-calcium second messenger system. Receptor for oxytocin.
• KEGG Pathway:
  Calcium signaling pathway (hsa04020)
  cAMP signaling pathway (hsa04024)
  Neuroactive ligand-receptor interaction (hsa04080)
  Oxytocin signaling pathway (hsa04921)
• Reactome Pathway:
  G alpha (q) signalling events (R-HSA-416476)
  Vasopressin-like receptors (R-HSA-388479)

Molecular Interaction Atlas (MIA) of This DTT

4 Approved Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
Carbetocin	DMUSLW3	Postpartum haemorrhage	JA43	Approved	[1], [2], [3]
Desmopressin	DMS3GVE	Diabetic complication	5A2Y	Approved	[4]
Oxytocin	DMDL27I	Autism spectrum disorder	6A02	Approved	[5], [6]
ATOSIBAN	DMB7WYM	N. A.	N. A.	Phase 4	[7]

5 Clinical Trial Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
Retosiban	DMOYGZF	Preterm labour	JB00	Phase 3	[8]
Barusiban	DMWI0X3	Androgen deficiency	5A81.1	Phase 2	[9]
FE-202767	DMDGZ1C	Erectile dysfunction	HA01.1	Phase 2	[5]
GSK-557296	DM3ZL2O	Premature ejaculation	HA03.0Z	Phase 2	[10]
SSR149415	DMCMD93	Anxiety disorder	6B00-6B0Z	Phase 2	[11]

10 Patented Agent(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
PMID28906174-Compound-figure1g	DMECU90	N. A.	N. A.	Patented	[12]
Pyrrolidine derivative 10	DMCQN5M	N. A.	N. A.	Patented	[12]
Pyrrolidine derivative 11	DMIHRV9	N. A.	N. A.	Patented	[12]
Pyrrolidine derivative 12	DMXO8R5	N. A.	N. A.	Patented	[12]
Pyrrolidine derivative 13	DM3VA8P	N. A.	N. A.	Patented	[12]
Pyrrolidine derivative 9	DMZK658	N. A.	N. A.	Patented	[12]
Triazole derivative 4	DMCFEAS	N. A.	N. A.	Patented	[12]
Triazole derivative 5	DMA83QK	N. A.	N. A.	Patented	[12]
Triazole derivative 6	DMU15FW	N. A.	N. A.	Patented	[12]
Triazole derivative 7	DMRK4AT	N. A.	N. A.	Patented	[12]

5 Discontinued Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
L-368899	DM5LRKC	Miscarriage	JA00.0	Discontinued in Phase 1	[13]
PF-3274167	DMD42MN	Female sexual arousal dysfunction	HA01.1	Discontinued in Phase 1	[14]
TT-235	DMHJXL6	Miscarriage	JA00.0	Discontinued in Phase 1	[15], [16]
AS-602305	DMH78J6	Androgen deficiency	5A81.1	Terminated	[17]
L-371257	DMCRQTH	N. A.	N. A.	Terminated	[14]

66 Investigative Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
1'-tosylspiro[indene-1,4'-piperidine]	DM9SYEP	Discovery agent	N.A.	Investigative	[14]
ARGENINE VASOPRESSIN	DM8KN0Q	Discovery agent	N.A.	Investigative	[18]
D(CH2)5[Tyr(Me)2,Thr4,Orn8(5/6C-Flu),Tyr-NH29]VT	DMVHMGA	Discovery agent	N.A.	Investigative	[19]
D(CH2)5[Tyr(Me)2,Thr4,Orn8,Tyr9-NH2]VT	DM1BMT7	Discovery agent	N.A.	Investigative	[19]
d(CH2)5[Tyr(Me)2]AVP	DMHTSAX	Discovery agent	N.A.	Investigative	[20]
DesGly-NH2,d(CH2)5[D-Tyr2,Thr4,Orn8(5/6C-Flu)]VT	DMJK0H5	Discovery agent	N.A.	Investigative	[19]
D[Arg4,Dab8]VP	DMCU8HK	Discovery agent	N.A.	Investigative	[18]
D[Arg4,Lys8]VP	DM69OVM	Discovery agent	N.A.	Investigative	[18]
D[Arg4,Orn8]VP	DM8D4QT	Discovery agent	N.A.	Investigative	[18]
D[Arg4]AVP	DM76Q2B	Discovery agent	N.A.	Investigative	[18]
D[Cha4,Dab8]VP	DMCLUXI	Discovery agent	N.A.	Investigative	[18]
D[Cha4,Dap8]VP	DMAPZKB	Discovery agent	N.A.	Investigative	[18]
D[Cha4,Lys8]VP	DM0GO7U	Discovery agent	N.A.	Investigative	[18]
D[Cha4,Orn8]VP	DMZWTJK	Discovery agent	N.A.	Investigative	[18]
D[Cha4]AVP	DM8FCX5	Discovery agent	N.A.	Investigative	[18]
D[Leu4,Dab8]VP	DMNSXG9	Discovery agent	N.A.	Investigative	[18]
D[Leu4,Dap8]VP	DME3HK8	Discovery agent	N.A.	Investigative	[18]
D[Leu4,Lys8]VP	DMDBU7Q	Discovery agent	N.A.	Investigative	[18]
D[Leu4,Orn8]VP	DMJCW8Y	Discovery agent	N.A.	Investigative	[18]
D[Leu4]AVP	DMREZT7	Discovery agent	N.A.	Investigative	[18]
D[Lys8(5/6-Flu)]VT	DME2PKB	Discovery agent	N.A.	Investigative	[19]
D[Orn4,Lys8]VP	DMNQTBU	Discovery agent	N.A.	Investigative	[18]
D[Orn4,Orn8]VP	DMONV0M	Discovery agent	N.A.	Investigative	[18]
D[Orn4]AVP	DMJNT95	Discovery agent	N.A.	Investigative	[18]
D[Orn8(5/6C-Flu)]VT	DMH791N	Discovery agent	N.A.	Investigative	[19]
D[Thr4,Lys8(5/6C-Flu)]VT	DMS4F8O	Discovery agent	N.A.	Investigative	[19]
D[Thr4,Orn8(5/6C-Flu)]VT	DMBDZQA	Discovery agent	N.A.	Investigative	[19]
D[Val4]AVP	DM3GM8E	Discovery agent	N.A.	Investigative	[18]
L-365,209	DM1WMHO	Discovery agent	N.A.	Investigative	[20]
L-366,509	DMGQE1B	Discovery agent	N.A.	Investigative	[20]
L-366,682	DMAS5P8	Discovery agent	N.A.	Investigative	[20]
L-366,948	DM31NXF	Discovery agent	N.A.	Investigative	[20]
L-367,773	DMQ369D	Discovery agent	N.A.	Investigative	[20]
L-372662	DMQV974	Discovery agent	N.A.	Investigative	[14]
L023103	DM9KWUR	Discovery agent	N.A.	Investigative	[21]
LS-192629	DMUBF53	Discovery agent	N.A.	Investigative	[22]
PF-271836	DMYSWAZ	Female sexual arousal dysfunction	HA01.1	Investigative	[5]
PMID16250654C37	DMIT4UN	Discovery agent	N.A.	Investigative	[23]
SSR126768A	DMF0X2S	Discovery agent	N.A.	Investigative	[24]
[35S]-non-peptide OT antagonist	DMSHOQ8	Discovery agent	N.A.	Investigative	[25]
[Aib7]OT	DMUCAXT	Discovery agent	N.A.	Investigative	[26]
[D-Tic7]OT	DME8W3R	Discovery agent	N.A.	Investigative	[26]
[Gly(But)7]OT	DMZM3GB	Discovery agent	N.A.	Investigative	[26]
[HO1][Lys8(5/6C-Flu)]VT	DMLZNK6	Discovery agent	N.A.	Investigative	[19]
[HO1][Orn8(5/6C-Flu)]VT	DMFK9V5	Discovery agent	N.A.	Investigative	[19]
[HO1][Orn8(5/6C-Rhm)]VT	DM7COAM	Discovery agent	N.A.	Investigative	[19]
[HO1][Thr4,Lys8(5/6C-Flu)]VT	DMT2UYR	Discovery agent	N.A.	Investigative	[19]
[HO1][Thr4,Orn8(5/6C-Flu)]VT	DM81B4W	Discovery agent	N.A.	Investigative	[19]
[L-Tic7]OT	DMHUMDR	Discovery agent	N.A.	Investigative	[26]
[Lys8(Alexa 488) ]PVA	DM7STF6	Discovery agent	N.A.	Investigative	[27]
[Lys8(Alexa 546) ]PVA	DM38L6U	Discovery agent	N.A.	Investigative	[27]
[Mpa1, D-Tic2, Aib7]OT	DM27LNU	Discovery agent	N.A.	Investigative	[26]
[Mpa1, D-Tic7]OT	DMPT1ME	Discovery agent	N.A.	Investigative	[26]
[Mpa1, D-Tyr(Et)2, Aib7, D-Tic9]OT	DMBPVSD	Discovery agent	N.A.	Investigative	[26]
[Mpa1, D-Tyr(Et)2, Aib7]OT	DMQSG6Y	Discovery agent	N.A.	Investigative	[26]
[Mpa1, D-Tyr(Et)2, D-Tic7, Aib9]OT	DM5GSXC	Discovery agent	N.A.	Investigative	[26]
[Mpa1, D-Tyr(Et)2, D-Tic7, D-Tic9]OT	DMI9MBO	Discovery agent	N.A.	Investigative	[26]
[Mpa1, D-Tyr(Et)2, D-Tic7]OT	DM3T4JF	Discovery agent	N.A.	Investigative	[26]
[Mpa1, D-Tyr(Et)2, Gly(But)3, Gly(But)7]OT	DML8V4F	Discovery agent	N.A.	Investigative	[26]
[Mpa1, D-Tyr(Et)2, Gly(But)7]OT	DMX2SU9	Discovery agent	N.A.	Investigative	[26]
[Mpa1, D-Tyr(Et)2, L-Tic7]OT	DM0H3NV	Discovery agent	N.A.	Investigative	[26]
[Mpa1, D-Tyr(Et)2, Pip7]OT	DM6W4LR	Discovery agent	N.A.	Investigative	[26]
[Mpa1, L-Tic7]OT	DMB4J3N	Discovery agent	N.A.	Investigative	[26]
[Phe3]OT	DMK18CS	Discovery agent	N.A.	Investigative	[28]
[Pip7]OT	DMXJDEA	Discovery agent	N.A.	Investigative	[26]
[Thr4,Gly7]OT	DM7QAKB	Discovery agent	N.A.	Investigative	[29]

References

• [1] Peptide and non-peptide agonists and antagonists for the vasopressin and oxytocin V1a, V1b, V2 and OT receptors: research tools and potential therapeutic agents. Prog Brain Res. 2008;170:473-512.
• [2] Structural organization of the human oxytocin receptor gene. J Biol Chem. 1994 Dec 23;269(51):32451-6.
• [3] Structure and expression of a human oxytocin receptor. Nature. 1992 Apr 9;356(6369):526-9.
• [4] Design of potent and selective agonists for the human vasopressin V1b receptor based on modifications of [deamino-cys1]arginine vasopressin at position 4. J Med Chem. 2004 Apr 22;47(9):2375-88.
• [5] 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: 369).
• [6] Oxytocin receptors and human parturition: a dual role for oxytocin in the initiation of labor. Science. 1982 Mar 12;215(4538):1396-8.
• [7] Pyridobenzodiazepines: a novel class of orally active, vasopressin V2 receptor selective agonists. Bioorg Med Chem Lett. 2006 Feb 15;16(4):954-9.
• [8] The Effect of an Oxytocin Receptor Antagonist (Retosiban, GSK221149A) on the Response of Human Myometrial Explants to Prolonged Mechanical Stretch.Endocrinology.2015 Oct;156(10):3511-6.
• [9] The effect of barusiban, a selective oxytocin antagonist, in threatened preterm labor at late gestational age: a randomized, double-blind, placebo-controlled trial. Am J Obstet Gynecol. 2009 Jun;200(6):627.e1-10.
• [10] Inhibition of ejaculation by the non-peptide oxytocin receptor antagonist GSK557296: a multi-level site of action. Br J Pharmacol. 2013 Aug;169(7):1477-85.
• [11] Tetrahydroquinoline sulfonamides as vasopressin 1b receptor antagonists. Bioorg Med Chem Lett. 2009 Nov 1;19(21):6018-22.
• [12] A patent review of oxytocin receptor antagonists 2013-2017.Expert Opin Ther Pat. 2017 Dec;27(12):1287-1290.
• [13] Pharmacokinetics and disposition of the oxytocin receptor antagonist L-368,899 in rats and dogs. Drug Metab Dispos. 1997 Oct;25(10):1113-8.
• [14] Oral oxytocin antagonists. J Med Chem. 2010 Sep 23;53(18):6525-38.
• [15] In vivo activity of the potent oxytocin antagonist on uterine activity in the rat. In Vivo. 2004 Nov-Dec;18(6):763-6.
• [16] Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health & Human Services. 2015
• [17] Clinical pipeline report, company report or official report of darkpharma.
• [18] Design and synthesis of the first selective agonists for the rat vasopressin V(1b) receptor: based on modifications of deamino-[Cys1]arginine vasop... J Med Chem. 2007 Feb 22;50(4):835-47.
• [19] Synthesis and characterization of fluorescent antagonists and agonists for human oxytocin and vasopressin V(1)(a) receptors. J Med Chem. 2002 Jun 6;45(12):2579-88.
• [20] Characterization of the human oxytocin receptor stably expressed in 293 human embryonic kidney cells. Life Sci. 1995;57(24):2253-61.
• [21] Discovery and development of a new class of potent, selective, orally active oxytocin receptor antagonists. J Med Chem. 2005 Dec 1;48(24):7882-905.
• [22] Pharmacology of (2S,4Z)-N-[(2S)-2-hydroxy-2-phenylethyl]-4-(methoxyimino) -1-[(2'-methyl[1,1'-biphenyl]-4-yl)carbonyl]-2-pyrrolidinecarboxamide, a ... J Pharmacol Exp Ther. 2003 Jul;306(1):253-61.
• [23] 2,5-diketopiperazines as potent, selective, and orally bioavailable oxytocin antagonists. 2. Synthesis, chirality, and pharmacokinetics. J Med Chem. 2005 Nov 3;48(22):6956-69.
• [24] SSR126768A (4-chloro-3-[(3R)-(+)-5-chloro-1-(2,4-dimethoxybenzyl)-3-methyl-2-oxo-2,3-dihydro-1H-indol-3-yl]-N-ethyl-N-(3-pyridylmethyl)-benzamide, ... J Pharmacol Exp Ther. 2004 Apr;309(1):414-24.
• [25] A nonpeptide oxytocin receptor antagonist radioligand highly selective for human receptors. Eur J Pharmacol. 2002 Aug 16;450(1):19-28.
• [26] Synthesis and biological activity of oxytocin analogues containing conformationally-restricted residues in position 7. Eur J Med Chem. 2007 Jun;42(6):799-806.
• [27] Toward efficient drug screening by homogeneous assays based on the development of new fluorescent vasopressin and oxytocin receptor ligands. J Med Chem. 2007 Oct 4;50(20):4976-85.
• [28] Two aromatic residues regulate the response of the human oxytocin receptor to the partial agonist arginine vasopressin. FEBS Lett. 1996 Nov 18;397(2-3):201-6.
• [29] [3H]-[Thr4,Gly7]OT: a highly selective ligand for central and peripheral OT receptors. Am J Physiol. 1988 Jan;254(1 Pt 1):E31-8.