Details of the Drug Therapeutic Target (DTT)

General Information of Drug Therapeutic Target (DTT) (ID: TTJ584C)

• DTT Name: Peroxisome proliferator-activated receptor alpha (PPARA)
• Synonyms: Peroxisome proliferater-activated receptor alpha; PPARalpha; PPAR-alpha; PPAR; Nuclear receptor subfamily 1 group C member 1; NR1C1
• Gene Name: PPARA
• DTT Type: Successful target; [1]
• BioChemical Class: Nuclear hormone receptor
• UniProt ID: PPARA_HUMAN
• TTD ID: T86591
• Sequence:
  MVDTESPLCPLSPLEAGDLESPLSEEFLQEMGNIQEISQSIGEDSSGSFGFTEYQYLGSC
  PGSDGSVITDTLSPASSPSSVTYPVVPGSVDESPSGALNIECRICGDKASGYHYGVHACE
  GCKGFFRRTIRLKLVYDKCDRSCKIQKKNRNKCQYCRFHKCLSVGMSHNAIRFGRMPRSE
  KAKLKAEILTCEHDIEDSETADLKSLAKRIYEAYLKNFNMNKVKARVILSGKASNNPPFV
  IHDMETLCMAEKTLVAKLVANGIQNKEAEVRIFHCCQCTSVETVTELTEFAKAIPGFANL
  DLNDQVTLLKYGVYEAIFAMLSSVMNKDGMLVAYGNGFITREFLKSLRKPFCDIMEPKFD
  FAMKFNALELDDSDISLFVAAIICCGDRPGLLNVGHIEKMQEGIVHVLRLHLQSNHPDDI
  FLFPKLLQKMADLRQLVTEHAQLVQIIKKTESDAALHPLLQEIYRDMY
• Function: Key regulator of lipid metabolism. Activated by the endogenous ligand 1-palmitoyl-2-oleoyl-sn-glycerol-3-phosphocholine (16:0/18:1-GPC). Activated by oleylethanolamide, a naturally occurring lipid that regulates satiety. Receptor for peroxisome proliferators such as hypolipidemic drugs and fatty acids. Regulates the peroxisomal beta-oxidation pathway of fatty acids. Functions as transcription activator for the ACOX1 and P450 genes. Transactivation activity requires heterodimerization with RXRA and is antagonized by NR2C2. May be required for the propagation of clock information to metabolic pathways regulated by PER2. Ligand-activated transcription factor.
• KEGG Pathway:
  PPAR signaling pathway (hsa03320)
  cAMP signaling pathway (hsa04024)
  Adipocytokine signaling pathway (hsa04920)
  Glucagon signaling pathway (hsa04922)
  Non-alcoholic fatty liver disease (NAFLD) (hsa04932)
  Hepatitis C (hsa05160)
• Reactome Pathway:
  BMAL1 (R-HSA-1368108)
  PPARA activates gene expression (R-HSA-1989781)
  YAP1- and WWTR1 (TAZ)-stimulated gene expression (R-HSA-2032785)
  Transcriptional activation of mitochondrial biogenesis (R-HSA-2151201)
  Activation of gene expression by SREBF (SREBP) (R-HSA-2426168)
  Transcriptional regulation of white adipocyte differentiation (R-HSA-381340)
  Nuclear Receptor transcription pathway (R-HSA-383280)
  Regulation of lipid metabolism by Peroxisome proliferator-activated receptor alpha (PPARalpha) (R-HSA-400206)
  Circadian Clock (R-HSA-400253)
  RORA activates gene expression (R-HSA-1368082)

Molecular Interaction Atlas (MIA) of This DTT

5 Approved Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
Bezafibrate	DMZDCS0	Hypercholesterolaemia	5C80.0	Approved	[2]
Ciprofibrate	DMGC5DB	Hyperlipoproteinemia	5C80	Approved	[1]
Fenofibrate	DMFKXDY	Coronary atherosclerosis		Approved	[1]
Lobeglitazone	DMHY3IP	Type-2 diabetes	5A11	Approved	[3]
Pemafibrate	DMD1VZL	Hyperlipidemia	5C80.Z	Approved	[4]

17 Clinical Trial Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
CS-038	DM67P0F	Type-2 diabetes	5A11	Phase 3	[5]
GFT-505	DM7ZOAE	Non-alcoholic steatohepatitis	DB92.1	Phase 3	[6]
Imiglitazar	DM7BCWT	Type-2 diabetes	5A11	Phase 3	[7]
MURAGLITAZAR	DMG3NFZ	N. A.	N. A.	Phase 3	[8]
Ragaglitazar	DMFSHEM	Type-1 diabetes	5A10	Phase 3	[9]
TESAGLITAZAR	DMGRBN5	Type-1 diabetes	5A10	Phase 3	[10]
ZYH-1	DMMBJYC	Lipid metabolism disorder	5C52.Z	Phase 3	[11]
GFT14	DMD3RU8	Hyperlipidaemia	5C80	Phase 2	[12]
LY-518674	DMBM2I9	Diabetic complication	5A2Y	Phase 2	[13]
Naveglitazar	DMD0E8U	Diabetic complication	5A2Y	Phase 2	[14]
ONO-5129	DMFX3P1	Diabetic complication	5A2Y	Phase 2	[15]
ZYH7	DMG7YI9	Dyslipidemia	5C80-5C81	Phase 2	[16]
AVE0897	DM56VG2	Type-2 diabetes	5A11	Phase 1	[17]
CDT-fenofibrate	DMKUXB5	Hyperlipidaemia	5C80	Phase 1	[18]
GW-409544	DMOE5SZ	Hyperlipidaemia	5C80	Phase 1	[19]
Oxeglitazar	DMN4LMT	Gout	FA25	Phase 1	[20]
TPST-1120	DMG4U32	Solid tumour/cancer	2A00-2F9Z	Phase 1	[21]

3 Patented Agent(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
Flavonoid derivative 8	DM4O9T3	N. A.	N. A.	Patented	[22]
PMID25416646-Compound-Figure5-A	DM9OHAN	N. A.	N. A.	Patented	[22]
PMID25416646-Compound-Figure5-H	DMCJTU1	N. A.	N. A.	Patented	[22]

22 Discontinued Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
Aleglitazar	DMTG18I	Type-2 diabetes	5A11	Discontinued in Phase 3	[23]
AVE-0847	DMRYK1C	Hyperlipidaemia	5C80	Discontinued in Phase 2	[24]
AVE-8134	DMCX6MD	Heart failure	BD10-BD13	Discontinued in Phase 2	[25]
BM-17.0744	DM7ZI8A	Type-1 diabetes	5A10	Discontinued in Phase 2	[26]
GSK-677954	DM5WRJX	Non-alcoholic fatty liver disease	DB92	Discontinued in Phase 2	[27]
Indeglitazar	DMS56UD	Type-2 diabetes	5A11	Discontinued in Phase 2	[28]
KRP-101	DMBU9O4	Hyperlipidaemia	5C80	Discontinued in Phase 2	[29]
KRP-297	DM9VHZC	Type-2 diabetes	5A11	Discontinued in Phase 2	[30]
NS-220	DMQ82T5	Hyperlipidaemia	5C80	Discontinued in Phase 2	[31]
Reglixane	DMIN73Y	Diabetic complication	5A2Y	Discontinued in Phase 2	[15]
Sodelglitazar	DMJ816F	Hyperlipidaemia	5C80	Discontinued in Phase 2	[32]
AR-H049020	DMHZN42	Type-1 diabetes	5A10	Discontinued in Phase 1	[33]
DRF 10945	DMOPM7L	Hyperlipidaemia	5C80	Discontinued in Phase 1	[34]
E-3030	DMJWR1I	Hyperlipidaemia	5C80	Discontinued in Phase 1	[35]
LG-101280	DM0PXGU	Arteriosclerosis	BD40	Discontinued in Phase 1	[36]
LY-929	DMVYG5X	Lipid metabolism disorder	5C52.Z	Discontinued in Phase 1	[37]
MP-136	DMK91WR	Lipid metabolism disorder	5C52.Z	Discontinued in Phase 1	[38]
BVT-142	DMIYPLU	Type-2 diabetes	5A11	Terminated	[42]
CS-204	DM1E7H3	Metabolic disorder	5C50-5D2Z	Terminated	[43]
CS-207	DMFJ4VT	Cardiovascular disease	BA00-BE2Z	Terminated	[44]
KRP-105	DMVZSAM	Lipid metabolism disorder	5C52.Z	Terminated	[45]
Sipoglitazar	DM5SBUJ	Diabetic complication	5A2Y	Terminated	[11]

4 Preclinical Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
MC-3001	DMLK2D0	Lipid metabolism disorder	5C52.Z	Preclinical	[39]
MC-3002	DM7UGY9	Metabolic disorder	5C50-5D2Z	Preclinical	[15]
PIRINIXIC ACID	DM82Y75	Pulmonary fibrosis	CB03.4	Preclinical	[40]
Romazarit	DMZOUX4	Rheumatoid arthritis	FA20	Preclinical	[41]

25 Investigative Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
(9Z,12E)-12-nitrooctadeca-9,12-dienoic acid	DM2REIN	Discovery agent	N.A.	Investigative	[46]
(E)-12-Nitrooctadec-12-enoic Acid	DMBQTZL	Discovery agent	N.A.	Investigative	[46]
(E)-13-Nitrooctadec-12-enoic Acid	DMF74GJ	Discovery agent	N.A.	Investigative	[46]
(E)-4-(3,5-dimethoxystyryl)phenol	DMYXI2V	Discovery agent	N.A.	Investigative	[38]
8S-HETE	DMT9SAC	Discovery agent	N.A.	Investigative	[47]
AD-5061	DM5WV13	Discovery agent	N.A.	Investigative	[7]
BMS-687453	DMYAPG5	Discovery agent	N.A.	Investigative	[48]
CP-775146	DMANV7R	Discovery agent	N.A.	Investigative	[49]
DB-900	DMGRUN1	Type-2 diabetes	5A11	Investigative	[50]
Deoxy-Bigchap	DMYAJCG	Discovery agent	N.A.	Investigative	[51]
DRF 2519	DMTFQG3	Discovery agent	N.A.	Investigative	[52]
eicosatetranoic acid	DMAKP20	Discovery agent	N.A.	Investigative	[53]
Fibrates	DMFNTMY	Dyslipidemia	5C80-5C81	Investigative	[54]
GSK-9578	DMW9AN1	Discovery agent	N.A.	Investigative	[1]
GW-2331	DMM8V9E	Discovery agent	N.A.	Investigative	[55]
GW7647	DM9RD0C	Discovery agent	N.A.	Investigative	[56]
L-165461	DMKBSGN	Discovery agent	N.A.	Investigative	[57]
L-796449	DMWTGQM	Discovery agent	N.A.	Investigative	[57]
LL-6531	DM6RCES	Diabetic complication	5A2Y	Investigative	[38]
LY-465608	DMK64AZ	Discovery agent	N.A.	Investigative	[58]
N-oleoylethanolamide	DMJQ4L7	Discovery agent	N.A.	Investigative	[59]
pristanic acid	DMTJZQK	Discovery agent	N.A.	Investigative	[60]
reglitazar	DMQ3ER0	Discovery agent	N.A.	Investigative	[61]
TZD18	DMVCHOX	Discovery agent	N.A.	Investigative	[62]
ZY H2	DMN9UCI	Discovery agent	N.A.	Investigative	[63]

Molecular Expression Atlas (MEA) of This DTT

Disease Name	ICD 11	Studied Tissue	p-value	Fold-Change	Z-score
Type 2 diabetes	5A11	Liver tissue	1.74E-01	-0.17	-0.3
Non-alcoholic fatty liver disease	DD91.0	Liver tissue	2.89E-01	-0.25	-0.67
Rheumatoid arthritis	FA20	Synovial tissue	1.12E-01	0.35	0.96
Coronary artery disease	BA80-BA8Z	Peripheral blood	1.54E-03	-0.29	-1.6

References

• [1] Peroxisome proliferator-activated receptor alpha activators improve insulin sensitivity and reduce adiposity. J Biol Chem. 2000 Jun 2;275(22):16638-42.
• [2] Bezafibrate at clinically relevant doses decreases serum/liver triglycerides via down-regulation of sterol regulatory element-binding protein-1c in... Mol Pharmacol. 2009 Apr;75(4):782-92.
• [3] Tolerability and pharmacokinetics of lobeglitazone, a novel peroxisome proliferator-activated receptor-gamma agonist, after a single oral administration in healthy female subjects. Clin Drug Investig. 2014 Jul;34(7):467-74.
• [4] Pemafibrate: First Global Approval. Drugs. 2017 Oct;77(16):1805-1810.
• [5] Determination of chiglitazar, a dual alpha/gamma peroxisome proliferator-activated receptor (PPAR) agonist, in human plasma by liquid chromatograph... Pharmazie. 2007 Nov;62(11):825-9.
• [6] Dual peroxisome proliferator-activated receptor / agonist GFT505 improves hepatic and peripheral insulin sensitivity in abdominally obese subjects.Diabetes Care.2013 Oct;36(10):2923-30.
• [7] A novel oxyiminoalkanoic acid derivative, TAK-559, activates human peroxisome proliferator-activated receptor subtypes. Eur J Pharmacol. 2004 Jul 8;495(1):17-26.
• [8] Muraglitazar, a dual (alpha/gamma) PPAR activator: a randomized, double-blind, placebo-controlled, 24-week monotherapy trial in adult patients with... Clin Ther. 2005 Aug;27(8):1181-95.
• [9] Ragaglitazar: the pharmacokinetics, pharmacodynamics, and tolerability of a novel dual PPAR alpha and gamma agonist in healthy subjects and patients with type 2 diabetes. J Clin Pharmacol. 2003 Nov;43(11):1244-56.
• [10] Tesaglitazar, a dual PPAR-/ agonist, hamster carcinogenicity, investigative animal and clinical studies.Toxicol Pathol.2012;40(1):18-32.
• [11] Pharmacokinetics, safety, and tolerability of saroglitazar (ZYH1), a predominantly PPARalpha agonist with moderate PPARgamma agonist activity in healthy human subjects. Clin Drug Investig. 2013 Nov;33(11):809-16.
• [12] Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800024296)
• [13] Potent and selective PPAR-alpha agonist LY518674 upregulates both ApoA-I production and catabolism in human subjects with the metabolic syndrome. Arterioscler Thromb Vasc Biol. 2009 Jan;29(1):140-6.
• [14] The disposition and metabolism of naveglitazar, a peroxisome proliferator-activated receptor alpha-gamma dual, gamma-dominant agonist in mice, rats... Drug Metab Dispos. 2007 Jan;35(1):51-61.
• [15] Interpreting expression profiles of cancers by genome-wide survey of breadth of expression in normal tissues. Genomics 2005 Aug;86(2):127-41.
• [16] Clinical pipeline report, company report or official report of Zydus Cadila.
• [17] Pharma & Vaccines. Product Development Pipeline. April 29 2009.
• [18] Mechanism of action of fibrates on lipid and lipoprotein metabolism. Circulation. 1998 Nov 10;98(19):2088-93.
• [19] Design novel dual agonists for treating type-2 diabetes by targeting peroxisome proliferator-activated receptors with core hopping approach. PLoS One. 2012;7(6):e38546.
• [20] Therapeutic potential of aleglitazar, a new dual PPAR-alpha/gamma agonist: implications for cardiovascular disease in patients with diabetes mellitus. Am J Cardiovasc Drugs. 2010;10(4):209-16.
• [21] Clinical pipeline report, company report or official report of Tempest Therapeutics.
• [22] PPAR ligands and their therapeutic applications: a patent review (2008 - 2014).Expert Opin Ther Pat. 2015 Feb;25(2):175-91.
• [23] Clinical pipeline report, company report or official report of Roche (2009).
• [24] DOI: 10.1038/scibx.2012.669
• [25] The peroxisome proliferator-activated receptor-alpha (PPAR-alpha) agonist, AVE8134, attenuates the progression of heart failure and increases survival in rats. Acta Pharmacol Sin. 2009 Jul;30(7):935-46.
• [26] Cardiac function and metabolism in Type 2 diabetic mice after treatment with BM 17.0744, a novel PPAR-alpha activator. Am J Physiol Heart Circ Physiol. 2002 Sep;283(3):H949-57.
• [27] Emerging drugs for non-alcoholic fatty liver disease. Expert Opin Emerg Drugs. 2008 Mar;13(1):145-58.
• [28] Scaffold-based discovery of indeglitazar, a PPAR pan-active anti-diabetic agent. Proc Natl Acad Sci U S A. 2009 Jan 6;106(1):262-7.
• [29] Identification of a functional peroxisome proliferator-activated receptor (PPAR) response element (PPRE) in the human apolipoprotein A-IV gene. Biochem Pharmacol. 2009 Sep 1;78(5):523-30.
• [30] KRP-297, MCC-555. Nihon Rinsho. 2001 Nov;59(11):2200-6.
• [31] Modulation of PPAR receptor subtype selectivity of the ligands: aliphatic chain vs aromatic ring as a spacer between pharmacophore and the lipophilic moiety. Bioorg Med Chem Lett. 2008 Dec 15;18(24):6471-5.
• [32] Docking and molecular dynamics simulations of peroxisome proliferator activated receptors interacting with pan agonist sodelglitazar. Protein Pept Lett. 2011 Oct;18(10):1021-7.
• [33] CN patent application no. 100577175, Combination therapy comprising glucose reabsorption inhibitors and PPAR modulators.
• [34] Peroxisome proliferator-activated receptors, metabolic syndrome and cardiovascular disease. Future Cardiol. 2010 September; 6(5): 657-691.
• [35] Antidiabetic and hypolipidemic effects of a novel dual peroxisome proliferator-activated receptor (PPAR) alpha/gamma agonist, E3030, in db/db mice and beagle dogs.J Pharmacol Sci.2008 Sep;108(1):40-8.
• [36] A peroxisome proliferator-activated receptor alpha/gamma dual agonist with a unique in vitro profile and potent glucose and lipid effects in rodent... Mol Endocrinol. 2005 Jun;19(6):1593-605.
• [37] CN patent application no. 1882326, Ppar agonists for the treatment of hcv infection.
• [38] 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: 593).
• [39] Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800021175)
• [40] O-arylmandelic acids as highly selective human PPAR alpha/gamma agonists. Bioorg Med Chem Lett. 2003 Oct 6;13(19):3185-90.
• [41] Fibrates as therapy for osteoarthritis and rheumatoid arthritis A systematic review. Ther Adv Musculoskelet Dis. 2013 February; 5(1): 33-44.
• [42] A new class of peroxisome proliferator-activated receptor agonists with a novel binding epitope shows antidiabetic effects. J Biol Chem. 2004 Sep 24;279(39):41124-30.
• [43] Peroxisome Proliferators-Activated Receptor (PPAR) Modulators and Metabolic Disorders. PPAR Res. 2008; 2008: 679137.
• [44] Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800026848)
• [45] Discovery of cyclic amine-substituted benzoic acids as PPARalpha agonists. Bioorg Med Chem Lett. 2012 Jan 1;22(1):334-8.
• [46] Activation of peroxisome proliferator-activated receptor gamma (PPARgamma) by nitroalkene fatty acids: importance of nitration position and degree ... J Med Chem. 2009 Aug 13;52(15):4631-9.
• [47] Differential activation of peroxisome proliferator-activated receptors by eicosanoids. J Biol Chem. 1995 Oct 13;270(41):23975-83.
• [48] Discovery of an oxybenzylglycine based peroxisome proliferator activated receptor alpha selective agonist 2-((3-((2-(4-chlorophenyl)-5-methyloxazol... J Med Chem. 2010 Apr 8;53(7):2854-64.
• [49] Molecular characterization of novel and selective peroxisome proliferator-activated receptor alpha agonists with robust hypolipidemic activity in vivo. Mol Pharmacol. 2009 Feb;75(2):296-306.
• [50] CN patent application no. 102459215, 3-(4-aminophenyl)-2-furancarboxylic acid derivative and pharmaceutically acceptable salt thereof.
• [51] How many drug targets are there Nat Rev Drug Discov. 2006 Dec;5(12):993-6.
• [52] Antidiabetic and hypolipidemic potential of DRF 2519--a dual activator of PPAR-alpha and PPAR-gamma. Eur J Pharmacol. 2004 May 3;491(2-3):195-206.
• [53] PPAR alpha structure-function relationships derived from species-specific differences in responsiveness to hypolipidemic agents. Biol Chem. 1997 Jul;378(7):651-5.
• [54] Emerging antidyslipidemic drugs. Expert Opin Emerg Drugs. 2008 Jun;13(2):363-81.
• [55] PPAR-alpha and -gamma but not -delta agonists inhibit airway inflammation in a murine model of asthma: in vitro evidence for an NF-kappaB-independe... Br J Pharmacol. 2003 May;139(1):163-71.
• [56] Identification of a subtype selective human PPARalpha agonist through parallel-array synthesis. Bioorg Med Chem Lett. 2001 May 7;11(9):1225-7.
• [57] Phenylacetic acid derivatives as hPPAR agonists. Bioorg Med Chem Lett. 2003 Apr 7;13(7):1277-80.
• [58] Design and synthesis of alpha-aryloxy-alpha-methylhydrocinnamic acids: a novel class of dual peroxisome proliferator-activated receptor alpha/gamma agonists. J Med Chem. 2004 May 6;47(10):2422-5.
• [59] Oleoylethanolamide, an endogenous PPAR-alpha agonist, lowers body weight and hyperlipidemia in obese rats. Neuropharmacology. 2005 Jun;48(8):1147-53.
• [60] Pristanic acid and phytanic acid: naturally occurring ligands for the nuclear receptor peroxisome proliferator-activated receptor alpha. J Lipid Res. 2000 Nov;41(11):1801-7.
• [61] Pharmacological profiles of a novel oral antidiabetic agent, JTT-501, an isoxazolidinedione derivative. Eur J Pharmacol. 1999 Jan 8;364(2-3):211-9.
• [62] A novel peroxisome proliferator-activated receptor alpha/gamma dual agonist demonstrates favorable effects on lipid homeostasis. Endocrinology. 2004 Apr;145(4):1640-8.
• [63] The ChEMBL database in 2017. Nucleic Acids Res. 2017 Jan 4;45(D1):D945-D954.