Target Information

Target General Infomation
Target ID
T61722
Former ID
TTDC00237
Target Name
Putative G-protein coupled receptor 44
Gene Name
PTGDR2
Synonyms
CD294; Chemoattractant receptor-homologous molecule expressed on Th2 cells; PTGDR2
Target Type
Clinical Trial
Disease Asthma; Chronic obstructive pulmonary disease [ICD9: 490-492, 493, 494-496; ICD10: J40-J44, J47, J45]
Allergy [ICD9: 995.3; ICD10: T78.4]
Asthma [ICD10: J45]
Allergic rhinitis [ICD9: 472.0, 477, 995.3; ICD10: J00, J30, J31.0, T78.4]
Allergic asthma [ICD9: 493, 995.3; ICD10: J45, T78.4]
Respiratory disease [ICD10: J00-J99]
Solid tumours [ICD9: 140-199, 210-229; ICD10: C00-D48]
Function
Receptor for prostaglandin D2 (PGD2). Coupled to the G(i)-protein. Receptor activation may result in pertussis toxin- sensitive decreases in cAMP levels and Ca(2+) mobilization. PI3K signaling is also implicated in mediating PTGDR2 effects. PGD2 induced receptor internalization. CRTH2 internalization can be regulated by diverse kinases such as, PKC, PKA, ADRBK1/GRK2, GPRK5/GRK5 and GRK6. Receptoractivation is responsible, at least in part, in immune regulation and allergic/inflammation responses.
BioChemical Class
GPCR rhodopsin
Target Validation
T61722
UniProt ID
Q9Y5Y4
Sequence
MSANATLKPLCPILEQMSRLQSHSNTSIRYIDHAAVLLHGLASLLGLVENGVILFVVGCR
MRQTVVTTWVLHLALSDLLASASLPFFTYFLAVGHSWELGTTFCKLHSSIFFLNMFASGF
LLSAISLDRCLQVVRPVWAQNHRTVAAAHKVCLVLWALAVLNTVPYFVFRDTISRLDGRI
MCYYNVLLLNPGPDRDATCNSRQVALAVSKFLLAFLVPLAIIASSHAAVSLRLQHRGRRR
PGRFVRLVAAVVAAFALCWGPYHVFSLLEARAHANPGLRPLVWRGLPFVTSLAFFNSVAN
PVLYVLTCPDMLRKLRRSLRTVLESVLVDDSELGGAGSSRRRRTSSTARSASPLALCSRP
EEPRGPARLLGWLLGSCAASPQTGPLNRALSSTSS
Drugs and Mode of Action
Drug(s) LAROPIPRANT Drug Info Phase 4 Discovery agent [1], [2]
Setipiprant Drug Info Phase 3 Asthma [3]
ADC-3680 Drug Info Phase 2 Allergic rhinitis [4]
AMG 853 Drug Info Phase 2 Asthma [5]
ARRY-502 Drug Info Phase 2 Allergic asthma [6]
AZD1981 Drug Info Phase 2 Asthma; Chronic obstructive pulmonary disease [7], [8]
OC-000459 Drug Info Phase 2 Allergy [9]
QAV-680 Drug Info Phase 2 Allergic rhinitis [10]
AM-211 Drug Info Phase 1 Asthma [11]
AM-461 Drug Info Phase 1 Respiratory disease [12]
AP-761 Drug Info Phase 1 Asthma [13]
MK-7246 Drug Info Phase 1 Respiratory disease [14]
PGF2alpha Drug Info Clinical trial Solid tumours [15]
AZD5985 Drug Info Discontinued in Phase 1 Asthma; Chronic obstructive pulmonary disease [16]
AZD8075 Drug Info Discontinued in Phase 1 Asthma; Chronic obstructive pulmonary disease [17]
RG-7185 Drug Info Discontinued in Phase 1 Asthma [18]
Agonist 13,14-dihydro-15-keto-PGD2 Drug Info [19]
13,14-dihydro-15-keto-PGF2alpha Drug Info [20]
15(R)-15-methyl-PGD2 Drug Info [19]
15(S)-15-methyl-PGD2 Drug Info [20]
15-deoxy-Delta12,14-PGD2 Drug Info [21]
15-deoxy-Delta12,14-PGJ2 Drug Info [21]
CAY 10471 Drug Info [22]
Delta12-PGJ2 Drug Info [20]
L-888,291 Drug Info [23]
PGD2 Drug Info [19]
PGD3 Drug Info [21]
PGF2alpha Drug Info [21]
PGJ2 Drug Info [20]
U46619 Drug Info [20]
[3H]PGD2 Drug Info [24]
Inhibitor 2-(2,4-diphenylthiazol-5-yl)acetic acid Drug Info [25]
2-(2-acetyl-4-bromophenoxy)acetic acid Drug Info [26]
2-(2-allyl-4-chlorophenoxy)acetic acid Drug Info [27]
2-(2-benzhydryl-4-phenylthiazol-5-yl)acetic acid Drug Info [28]
2-(2-benzoyl-4-bromophenoxy)acetic acid Drug Info [26]
2-(2-cyclohexyl-4-fluorophenoxy)acetic acid Drug Info [27]
2-(2-cyclohexyl-4-methoxyphenoxy)acetic acid Drug Info [27]
2-(2-cyclohexyl-4-methylphenoxy)acetic acid Drug Info [27]
2-(2-cyclohexylphenoxy)acetic acid Drug Info [27]
2-(2-formylphenoxy)acetic acid Drug Info [26]
2-(4-bromo-2-(hydroxymethyl)phenoxy)acetic acid Drug Info [26]
2-(4-bromo-2-cyclohexylphenoxy)acetic acid Drug Info [27]
2-(4-bromo-2-formylphenoxy)acetic acid Drug Info [26]
2-(4-bromo-2-tert-butylphenoxy)acetic acid Drug Info [26]
2-(4-chloro-2-cycloheptylphenoxy)acetic acid Drug Info [29]
2-(4-chloro-2-cyclohexylphenoxy)acetic acid Drug Info [27]
2-(4-chloro-2-cyclopentylphenoxy)acetic acid Drug Info [27]
2-(4-cyano-2-cyclohexylphenoxy)acetic acid Drug Info [27]
3-(4-chloro-2-cyclohexylphenoxy)propanoic acid Drug Info [27]
4-(4-chloro-2-cyclohexylphenoxy)butanoic acid Drug Info [27]
IW-1221 Drug Info [30]
L-888607 Drug Info [31]
LAROPIPRANT Drug Info [32]
Methyl 2-(4-chloro-2-cyclohexylphenoxy)acetate Drug Info [27]
Antagonist ADC-3680 Drug Info [33]
ADC-9971 Drug Info [30]
AM-156 Drug Info [30]
AM-211 Drug Info [34]
AM-461 Drug Info [35]
AP-761 Drug Info [36]
AZD1981 Drug Info [37]
AZD5985 Drug Info [37]
AZD8075 Drug Info [37]
CRTH2 antagonists Drug Info [30]
CRTh2 receptor antagonists Drug Info [30]
CRTh2 receptor antagonists Drug Info [30]
OC-000459 Drug Info [38]
QAV-680 Drug Info [39]
RG-7185 Drug Info [40]
Setipiprant Drug Info [41]
TM-30089 Drug Info [30]
[3H]ramatroban Drug Info [19]
Modulator AMG 853 Drug Info
ARRY-502 Drug Info [42]
MK-7246 Drug Info [43]
Target Expression Profile (TEP) and Drug Resistance Mutation (DRM)
TEP EXP Info
Pathways
Reactome Prostanoid ligand receptors
G alpha (i) signalling events
WikiPathways GPCRs, Class A Rhodopsin-like
GPCR ligand binding
GPCR downstream signaling
References
REF 1ClinicalTrials.gov (NCT01126073) Niacin/Laropiprant and Endothelial Function. U.S. National Institutes of Health.
REF 2(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. (Ligand id: 3356).
REF 3ClinicalTrials.gov (NCT01484119) Efficacy, Safety, and Tolerability Study of ACT-129968 in Patients With Seasonal Allergic Rhinitis. U.S. National Institutes of Health.
REF 4ClinicalTrials.gov (NCT01448954) A Study to Evaluate Safety, Tolerability and Pharmacokinetics of ADC3680B in Subjects With Partly Controlled Atopic Asthma. U.S. National Institutes of Health.
REF 5ClinicalTrials.gov (NCT01018550) AMG 853 Phase 2 Study in Subjects With Inadequately Controlled Asthma. U.S. National Institutes of Health.
REF 6ClinicalTrials.gov (NCT01561690) A Study of ARRY-502 in Patients With Persistent Asthma. U.S. National Institutes of Health.
REF 7ClinicalTrials.gov (NCT00766415) 14729-D9831C00002- 1 Month Biopsy Study. U.S. National Institutes of Health.
REF 8(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. (Ligand id: 7680).
REF 9ClinicalTrials.gov (NCT01056783) Proof of Concept Study of OC000459 in Eosinophilic Esophagitis. U.S. National Institutes of Health.
REF 10ClinicalTrials.gov (NCT01103037) Efficacy, Safety and Pharmacokinetics of QAV680 Versus Placebo in Patients With Asthma. U.S. National Institutes of Health.
REF 11Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800030063)
REF 12Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800031337)
REF 13Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800028464)
REF 14Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800031315)
REF 15Stereocontrolled organocatalytic synthesis of prostaglandin PGF2alpha in seven steps. Nature. 2012 Sep 13;489(7415):278-81.
REF 16Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800029299)
REF 17Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800029210)
REF 18Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800033115)
REF 19CRTH2-specific binding characteristics of [3H]ramatroban and its effects on PGD2-, 15-deoxy-Delta12, 14-PGJ2- and indomethacin-induced agonist responses. Eur J Pharmacol. 2005 Nov 7;524(1-3):30-7. Epub 2005 Oct 27.
REF 20Molecular pharmacology of the human prostaglandin D2 receptor, CRTH2. Br J Pharmacol. 2002 Dec;137(8):1163-72.
REF 21Expression and molecular pharmacology of the mouse CRTH2 receptor. J Pharmacol Exp Ther. 2003 Aug;306(2):463-70. Epub 2003 Apr 29.
REF 22Minor structural modifications convert the dual TP/CRTH2 antagonist ramatroban into a highly selective and potent CRTH2 antagonist. J Med Chem. 2005 Feb 24;48(4):897-900.
REF 23Identification of a potent and selective synthetic agonist at the CRTH2 receptor. Mol Pharmacol. 2005 Jun;67(6):1834-9. Epub 2005 Mar 8.
REF 24On the mechanism of interaction of potent surmountable and insurmountable antagonists with the prostaglandin D2 receptor CRTH2. Mol Pharmacol. 2006 Apr;69(4):1441-53. Epub 2006 Jan 17.
REF 25Bioorg Med Chem Lett. 2010 Feb 1;20(3):1177-80. Epub 2009 Dec 4.Novel selective thiazoleacetic acids as CRTH2 antagonists developed from in silico derived hits. Part 1.
REF 26J Med Chem. 2006 Nov 16;49(23):6638-41.Novel selective orally active CRTH2 antagonists for allergic inflammation developed from in silico derived hits.
REF 27Bioorg Med Chem Lett. 2007 Aug 1;17(15):4347-50. Epub 2007 May 13.2-Cycloalkyl phenoxyacetic acid CRTh2 receptor antagonists.
REF 28Bioorg Med Chem Lett. 2010 Feb 1;20(3):1181-5. Epub 2009 Dec 6.Novel selective thiazoleacetic acids as CRTH2 antagonists developed from in silico derived hits. Part 2.
REF 29Bioorg Med Chem Lett. 2009 Aug 15;19(16):4794-8. Epub 2009 Jun 14.7-Azaindole-3-acetic acid derivatives: potent and selective CRTh2 receptor antagonists.
REF 30(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: 339).
REF 31J Med Chem. 2005 Oct 6;48(20):6174-7.Indole-3-acetic acid antagonists of the prostaglandin D2 receptor CRTH2.
REF 32J Med Chem. 2007 Feb 22;50(4):794-806.Discovery of a potent and selective prostaglandin D2 receptor antagonist, [(3R)-4-(4-chloro-benzyl)-7-fluoro-5-(methylsulfonyl)-1,2,3,4-tetrahydrocyclopenta[b]indol-3-yl]-acetic acid (MK-0524).
REF 33Update on the status of DP2 receptor antagonists; from proof of concept through clinical failures to promising new drugs. Expert Opin Investig Drugs. 2014 Jan;23(1):55-66.
REF 34Pharmacology of AM211, a potent and selective prostaglandin D2 receptor type 2 antagonist that is active in animal models of allergic inflammation. J Pharmacol Exp Ther. 2011 Jul;338(1):290-301.
REF 35A novel DP2 receptor antagonist (AM-461): a patent evaluation of WO2011085033. Expert Opin Ther Pat. 2011 Dec;21(12):1931-6.
REF 36Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800028464)
REF 37Clinical pipeline report, company report or official report of AstraZeneca (2009).
REF 38Anti-eosinophil activity and clinical efficacy of the CRTH2 antagonist OC000459 in eosinophilic esophagitis. Allergy. 2013 Mar;68(3):375-85.
REF 39Discovery and characterization of NVP-QAV680, a potent and selective CRTh2 receptor antagonist suitable for clinical testing in allergic diseases. Bioorg Med Chem. 2013 Nov 1;21(21):6582-91.
REF 40Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800033115)
REF 41Setipiprant, a selective CRTH2 antagonist, reduces allergen-induced airway responses in allergic asthmatics. Clin Exp Allergy. 2014 Aug;44(8):1044-52.
REF 42Clinical pipeline report, company report or official report of Array BioPharma (Drug: ARRY-502).
REF 43Discovery of MK-7246, a selective CRTH2 antagonist for the treatment of respiratory diseases. Bioorg Med Chem Lett. 2011 Jan 1;21(1):288-93.

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