Details of the Drug Therapeutic Target (DTT)

General Information of Drug Therapeutic Target (DTT) (ID: TTQL5VC)

• DTT Name: Platelet-activating factor receptor (PTAFR)
• Synonyms: PTAFR; PAF-R
• Gene Name: PTAFR
• DTT Type: Successful target; [1]
• BioChemical Class: GPCR rhodopsin
• UniProt ID: PTAFR_HUMAN
• TTD ID: T87023
• Sequence:
  MEPHDSSHMDSEFRYTLFPIVYSIIFVLGVIANGYVLWVFARLYPCKKFNEIKIFMVNLT
  MADMLFLITLPLWIVYYQNQGNWILPKFLCNVAGCLFFINTYCSVAFLGVITYNRFQAVT
  RPIKTAQANTRKRGISLSLVIWVAIVGAASYFLILDSTNTVPDSAGSGNVTRCFEHYEKG
  SVPVLIIHIFIVFSFFLVFLIILFCNLVIIRTLLMQPVQQQRNAEVKRRALWMVCTVLAV
  FIICFVPHHVVQLPWTLAELGFQDSKFHQAINDAHQVTLCLLSTNCVLDPVIYCFLTKKF
  RKHLTEKFYSMRSSRKCSRATTDTVTEVVVPFNQIPGNSLKN
• Function: Receptor for platelet activating factor, a chemotactic phospholipid mediator that possesses potent inflammatory, smooth- muscle contractile and hypotensive activity. Seems to mediate its action via a G protein that activates a phosphatidylinositol- calcium second messenger system.
• KEGG Pathway:
  Calcium signaling pathway (hsa04020)
  Neuroactive ligand-receptor interaction (hsa04080)
  Staphylococcus aureus infection (hsa05150)
• Reactome Pathway:
  G alpha (q) signalling events (R-HSA-416476)
  Interferon gamma signaling (R-HSA-877300)
  Class A/1 (Rhodopsin-like receptors) (R-HSA-373076)

Molecular Interaction Atlas (MIA) of This DTT

2 Approved Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
Ticlopidine	DMO946V	Acute coronary syndrome	BA41	Approved	[1]
RUPATADINE	DMBPN7T	N. A.	N. A.	Phase 4	[2]

7 Clinical Trial Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
ISRAPAFANT	DMP61YB	Asthma	CA23	Phase 3	[3]
60P002	DMHBN8X	Dengue	1D20-1D2Z	Phase 2	[4]
CMI-392	DM1NCUY	Psoriasis vulgaris	EA90	Phase 2	[5]
Dersalazine	DMH96JW	Inflammatory bowel disease	DD72	Phase 2	[6]
Lexipafant	DMZ2YBE	Nerve injury	ND56.4	Phase 2	[7]
YM-264	DMAZNVX	Sepsis	1G40-1G41	Phase 2	[8]
PegCNTF	DMW7VGZ	Obesity	5B81	Phase 1	[9]

33 Discontinued Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
BN 50730	DMZK70E	Asthma	CA23	Discontinued in Phase 3	[10]
FOROPAFANT	DML1DGP	Asthma	CA23	Discontinued in Phase 3	[11]
BN50727	DMC35T1	Inflammatory bowel disease	DD72	Discontinued in Phase 2	[12]
DE-081	DM3AVO1	Conjunctivitis	9A60	Discontinued in Phase 2	[13]
E-6123	DMUW6QX	Asthma	CA23	Discontinued in Phase 2	[14]
Minopafant	DMVF2R1	Sepsis	1G40-1G41	Discontinued in Phase 2	[15]
MK-287	DMCAKPG	Sepsis	1G40-1G41	Discontinued in Phase 2	[16]
Ro-24-4736	DM01MRZ	Sepsis	1G40-1G41	Discontinued in Phase 2	[17]
SM-10661	DMZYGW0	Sepsis	1G40-1G41	Discontinued in Phase 2	[18]
TCV-309	DM3VZ87	Sepsis	1G40-1G41	Discontinued in Phase 2	[19]
UK-74505	DMAD1S5	Sepsis	1G40-1G41	Discontinued in Phase 2	[20]
ABT-299	DM8GZAS	Sepsis	1G40-1G41	Discontinued in Phase 1	[21]
AGN-191743	DM8XODL	Allergy	4A80-4A85	Discontinued in Phase 1	[22]
DACOPAFANT	DMDUZ5W	Sepsis	1G40-1G41	Discontinued in Phase 1	[23]
DF-1111301	DMZYVFH	Allergy	4A80-4A85	Discontinued in Phase 1	[24]
SDZ-62-434	DMU3TQJ	Solid tumour/cancer	2A00-2F9Z	Discontinued in Phase 1	[25]
Bepafant	DMVK78Q	Sepsis	1G40-1G41	Terminated	[26]
BN-50726	DMTKJDS	Nerve injury	ND56.4	Terminated	[27]
BN50739	DMU1TRQ	Cerebral infarction	8B11.5Z	Terminated	[28]
CL-184005	DMJBGI1	Sepsis	1G40-1G41	Terminated	[29]
CMI-206	DMEIW7K	Inflammation	1A00-CA43.1	Terminated	[30]
CV 6209	DMQBULC	Asthma	CA23	Terminated	[31]
FR-128998	DMMOBHW	Thrombocytopenia	3B64	Terminated	[32]
KC-11404	DM3H90W	Asthma	CA23	Terminated	[33]
KC-11425	DMC295V	Asthma	CA23	Terminated	[34]
L-659989	DMLENQ7	N. A.	N. A.	Terminated	[35]
Ro-24-0238	DMJQA0D	Sepsis	1G40-1G41	Terminated	[36]
Sch-40338	DM3G5IB	Allergy	4A80-4A85	Terminated	[37]
SDZ-64-412	DM2CBTU	N. A.	N. A.	Terminated	[38]
TIAPAFANT	DM0SCDB	Sepsis	1G40-1G41	Terminated	[39]
TULOPAFANT	DMASENP	Cardiac arrhythmias	BC9Z	Terminated	[40]
UR-12460	DMV8GUE	Thrombosis	DB61-GB90	Terminated	[41]
WEB-2347	DMY9NG1	Allergy	4A80-4A85	Terminated	[42]

32 Investigative Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
10-OBn-7alpha-F-gingkolide B	DMM9GEA	Discovery agent	N.A.	Investigative	[43]
10-OBn-epi-ginkgolide C	DMAM5WJ	Discovery agent	N.A.	Investigative	[43]
10-OBn-ginkgolide B	DMS0I5V	Discovery agent	N.A.	Investigative	[43]
10-OBn-ginkgolide C	DMOXKLH	Discovery agent	N.A.	Investigative	[43]
2-O-ethyl-PAF C-16	DMZK0JV	Discovery agent	N.A.	Investigative	[44]
2-O-methyl-PAF C-18	DME7K64	Discovery agent	N.A.	Investigative	[44]
7-epi-ginkgolide C	DMRAZDW	Discovery agent	N.A.	Investigative	[43]
7alpha-Cl-ginkgolide B	DMD6UC9	Discovery agent	N.A.	Investigative	[43]
7alpha-F-ginkgolide B	DMRQ24A	Discovery agent	N.A.	Investigative	[43]
7alpha-N3-ginkgolide B	DMGNWBV	Discovery agent	N.A.	Investigative	[43]
7alpha-NH2-ginkgolide B	DMZUYX1	Discovery agent	N.A.	Investigative	[43]
7alpha-NHEt-ginkgolide B	DMWAB7F	Discovery agent	N.A.	Investigative	[43]
7alpha-NHMe-ginkgolide B	DMSPLYF	Discovery agent	N.A.	Investigative	[43]
7alpha-OAc-ginkgolide B	DMN1U56	Discovery agent	N.A.	Investigative	[43]
7alpha-OCOCH2Ph-ginkgolide B	DMGAPCD	Discovery agent	N.A.	Investigative	[43]
A 137491	DM1H3FJ	Discovery agent	N.A.	Investigative	[45]
BB-823	DMZPL63	Discovery agent	N.A.	Investigative	[41]
CV-3988	DMM7RAD	Discovery agent	N.A.	Investigative	[46]
enantio PAF C-16	DMASQWV	Discovery agent	N.A.	Investigative	[44]
FR-900452	DMMGWXQ	Discovery agent	N.A.	Investigative	[47]
KO-286011	DMVGNZJ	Discovery agent	N.A.	Investigative	[48]
L-652731	DM360VU	Discovery agent	N.A.	Investigative	[35]
LAU-0901	DMMDZ4B	Brain ischaemia	8B1Z	Investigative	[49]
methylcarbamyl PAF	DMV865Q	Discovery agent	N.A.	Investigative	[50]
PAF	DMRZAQW	Discovery agent	N.A.	Investigative	[51]
RP-52770	DM5IXOS	Discovery agent	N.A.	Investigative	[52]
SRI-63-675	DM8GDZS	Discovery agent	N.A.	Investigative	[53]
UR-10324	DMPF1VU	Discovery agent	N.A.	Investigative	[54]
UR-11353	DM8G9NY	Discovery agent	N.A.	Investigative	[54]
UR-12510	DM2HVUW	Allergy	4A80-4A85	Investigative	[55]
UR-12519	DMVZQ47	Discovery agent	N.A.	Investigative	[56]
VERAGUENSIN	DMJRVBS	Discovery agent	N.A.	Investigative	[35]

Molecular Expression Atlas (MEA) of This DTT

Disease Name	ICD 11	Studied Tissue	p-value	Fold-Change	Z-score
Psoriasis	EA90	Skin	5.94E-02	0.08	0.17
Asthma	CA23	Nasal and bronchial airway	3.75E-05	0.25	0.35
Thrombocytopenia	3B64	Whole blood	4.42E-01	0.49	1.01
Sepsis with septic shock	1G41	Whole blood	2.87E-10	0.6	0.77
Sjogren's syndrome	4A43.2	Salivary gland tissue	3.53E-02	0.33	2.12

References

• [1] Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health & Human Services.
• [2] Designed multiple ligands. An emerging drug discovery paradigm. J Med Chem. 2005 Oct 20;48(21):6523-43.
• [3] Amino acid residues critical for endoplasmic reticulum export and trafficking of platelet-activating factor receptor. J Biol Chem. 2010 Feb 19;285(8):5931-40.
• [4] Clinical pipeline report, company report or official report of 60 Degrees Pharmaceuticals.
• [5] Anti-inflammatory activities of LDP-392, a dual PAF receptor antagonist and 5-lipoxygenase inhibitor. Pharmacol Res. 2001 Sep;44(3):213-20.
• [6] The intestinal anti-inflammatory effect of dersalazine sodium is related to a down-regulation in IL-17 production in experimental models of rodent colitis. Br J Pharmacol. 2012 February; 165(3): 729-740.
• [7] Lexipafant and acute pancreatitis: a critical appraisal of the clinical trials.Eur J Surg.2002;168(4):215-9.
• [8] Effects of YM264, a novel PAF antagonist, on puromycin aminonucleoside-induced nephropathy in the rat. Biochem Biophys Res Commun. 1991 Apr 30;176(2):781-5.
• [9] Sch 37370: a new drug combining antagonism of platelet-activating factor (PAF) with antagonism of histamine. Agents Actions Suppl. 1991;34:313-21.
• [10] Platelet-activating factor antagonist BN 50730 attenuates hypoxic-ischemic brain injury in neonatal rats. Pediatr Res. 2001 Jun;49(6):804-11.
• [11] Biochemical and pharmacological activities of SR 27417, a highly potent, long-acting platelet-activating factor receptor antagonist. J Pharmacol Exp Ther. 1991 Oct;259(1):44-51.
• [12] Platelet-activating factor preferentially stimulates the phospholipase A2/cyclooxygenase cascade in the rabbit cornea. Curr Eye Res. 1995 Sep;14(9):769-75.
• [13] Characterization of [3H]apafant binding to PAF receptor on rabbit platelet membranes: a comparison of a microplate filtration system and a standard... J Pharmacol Toxicol Methods. 1996 Sep;36(1):53-62.
• [14] Inhibitory effects of a novel PAF antagonist E6123 on anaphylactic responses in passively and actively sensitized guinea pigs and passively sensiti... Prostaglandins. 1991 Dec;42(6):541-55.
• [15] Formation of spherical micelles composed of the novel platelet activating factor receptor antagonist, E5880. Pharm Dev Technol. 2005;10(1):11-6.
• [16] MK 287: a potent, specific, and orally active receptor antagonist of platelet-activating factor. J Lipid Mediat. 1993 Jun;7(2):115-34.
• [17] Pharmacology of a potent platelet-activating factor antagonist: Ro 24-4736. J Pharmacol Exp Ther. 1991 Oct;259(1):78-85.
• [18] Effect of the PAF-receptor antagonist SM-12502 on human platelets. Inflammation. 1996 Feb;20(1):71-85.
• [19] Inhibitory effect of TCV-309, a novel platelet activating factor (PAF) antagonist, on endotoxin-induced disseminated intravascular coagulation in r... Thromb Res. 1993 May 15;70(4):281-93.
• [20] Differential effects of the PAF receptor antagonist UK-74,505 on neutrophil and eosinophil accumulation in guinea-pig skin. Br J Pharmacol. 1994 Oct;113(2):513-21.
• [21] ABT-299, a novel PAF antagonist, attenuates multiple effects of endotoxemia in conscious rats. Shock. 1996 Aug;6(2):112-7.
• [22] US patent application no. 6,274,627, Conjugates of dithiocarbamate disulfides with pharmacologically active agents and uses therefor.
• [23] RP 55778, a PAF receptor antagonist, prevents and reverses LPS-induced hemoconcentration and TNF release. J Lipid Mediat. 1989 Nov-Dec;1(6):349-60.
• [24] US patent application no. 2007,0196,421, Soft tissue implants and drug combination compositions, and use thereof.
• [25] In vitro antitumour activity of the novel imidazoisoquinoline SDZ 62-434. Br J Cancer. 1993 May;67(5):989-95.
• [26] Pharmacologic activity of bepafant (WEB 2170), a new and selective hetrazepinoic antagonist of platelet activating factor. J Pharmacol Exp Ther. 1990 Dec;255(3):962-8.
• [27] Effects of the PAF antagonists BN50726 and BN50739 on arrhythmogenesis and extent of necrosis during myocardial ischaemia/reperfusion in rabbits. Br J Pharmacol. 1992 Nov;107(3):705-9.
• [28] Effect of the platelet-activating factor antagonist BN 50739 and its diluents on mitochondrial respiration and membrane lipids during and following... J Neurochem. 1994 May;62(5):1929-38.
• [29] Studies of the effect of a platelet-activating factor antagonist, CL 184,005, in animal models of gram-negative bacterial sepsis. Antimicrob Agents Chemother. 1992 Sep;36(9):1971-7.
• [30] DOI: 10.1016/0960-894X(95)00088-B
• [31] CV-6209, a highly potent antagonist of platelet activating factor in vitro and in vivo. J Pharmacol Exp Ther. 1987 Jul;242(1):263-8.
• [32] Effect of FR128998, a novel PAF receptor antagonist, on endotoxin-induced disseminated intravascular coagulation. Eur J Pharmacol. 1994 Jun 13;258(3):239-46.
• [33] Synthesis, structure-activity relationships, and pharmacological evaluation of pyrrolo[3,2,1-ij]quinoline derivatives: potent histamine and platelet activating factor antagonism and 5-lipoxygenase inhibitory properties. Potential therapeutic application in asthma. J Med Chem. 1995 Feb 17;38(4):669-85.
• [34] WO patent application no. 2002,01223,5, 1,4-dihydropyridines as bradykinin antagonists.
• [35] Development, synthesis, and biological evaluation of (-)-trans-(2S,5S)-2-[3-[(2-oxopropyl)sulfonyl]-4-n-propoxy-5-(3- hydroxypropoxy)-phenyl]-5-(3,... J Med Chem. 1992 Sep 18;35(19):3474-82.
• [36] Pentadienyl carboxamide derivatives as antagonists of platelet-activating factor. J Med Chem. 1989 Aug;32(8):1820-35.
• [37] Conformational considerations in the design of dual antagonists of platelet-activating factor (PAF) and histamine. Bioorg Med Chem. 1999 Jul;7(7):1413-23.
• [38] Structural modification of 5-aryl-2,3-dihydroimidazo[2,1-a]isoquinoline platelet activating factor receptor antagonists. J Med Chem. 1993 Oct 15;36(21):3098-102.
• [39] PCA-4248, a PAF receptor antagonist, inhibits PAF-induced phosphoinositide turnover. Eur J Pharmacol. 1995 Aug 15;290(3):183-8.
• [40] Tulopafant, a PAF receptor antagonist, increases capillary patency and prolongs survival in discordant cardiac xenotransplants. J Lipid Mediat. 1993 May;7(1):79-84.
• [41] Platelet-activating factor: the effector of protein-rich plasma extravasation and nitric oxide synthase induction in rat immune complex peritonitis. Br J Pharmacol. 1995 Feb;114(4):895-901.
• [42] WEB 2347: pharmacology of a new very potent and long acting hetrazepinoic PAF-antagonist and its action in repeatedly sensitized guinea-pigs. J Lipid Mediat. 1991 Jul-Aug;4(1):39-44.
• [43] Preparation of 7-substituted ginkgolide derivatives: potent platelet activating factor (PAF) receptor antagonists. J Med Chem. 2003 Feb 13;46(4):601-8.
• [44] A radioreceptor binding assay for platelet-activating factor (PAF) using membranes from CHO cells expressing human PAF receptor. J Immunol Methods. 1995 Oct 26;186(2):225-31.
• [45] The role of platelet-activating factor (PAF) and the efficacy of ABT-491, a highly potent and selective PAF antagonist, in experimental allergic rhinitis. J Pharmacol Exp Ther. 1998 Jan;284(1):83-8.
• [46] Inhibition by CV-3988 of the binding of [3H]-platelet activating factor (PAF) to the platelet. Biochem Pharmacol. 1985 May 1;34(9):1491-5.
• [47] FR-900452, a specific antagonist of platelet activating factor (PAF) produced by Streptomyces phaeofaciens. I. Taxonomy, fermentation, isolation, a... J Antibiot (Tokyo). 1986 Feb;39(2):198-204.
• [48] Platelet-activating factor (PAF) inhibitory profile of KO-286011 on blood platelets in vitro and in vivo. Naunyn Schmiedebergs Arch Pharmacol. 1990 Dec;342(6):713-8.
• [49] Superior Neuroprotective Efficacy of LAU-0901, a Novel Platelet-Activating Factor Antagonist, in Experimental Stroke. Transl Stroke Res. 2012 Mar;3(1):154-63.
• [50] 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: 334).
• [51] Identification of transmembrane domain residues determinant in the structure-function relationship of the human platelet-activating factor receptor by site-directed mutagenesis. J Biol Chem. 1996 Sep20;271(38):23298-303.
• [52] [3H]52770 RP, a platelet-activating factor receptor antagonist, and tritiated platelet-activating factor label a common specific binding site in human polymorphonuclear leukocytes. J Pharmacol Exp Ther. 1988 Feb;244(2):709-15.
• [53] The effect of SRI 63-675, a competitive platelet-activating factor receptor-antagonist, in the generalized Shwartzman reaction. J Lipid Mediat Cell Signal. 1994 Sep;10(3):229-42.
• [54] Effects of PAF-antagonists in mouse ear oedema induced by several inflammatory agents. Br J Pharmacol. 1991 Dec;104(4):990-4.
• [55] US patent application no. 6,673,908, Tumor necrosis factor receptor 2.
• [56] Evidence for the autocrine induction of capacitation of mammalian spermatozoa.J Biol Chem.2001 Jul 20;276(29):26962-8.