Muraglitazar

Muraglitazar
Clinical data
Other names	2-[(4-Methoxyphenoxy)carbonyl-[[4-[2-(5-methyl-2-phenyl-1,3-oxazol-4-yl)ethoxy]phenyl]methyl]amino]acetic acid
ATC code	None;
Legal status
Legal status	Development terminated;
Identifiers
	IUPAC name N-[(4-Methoxyphenoxy)carbonyl]-N-{4-[2-(5-methyl-2-phenyl-1,3-oxazol-4-yl)ethoxy]benzyl}glycine;
CAS Number	331741-94-7 ;
PubChem CID	206044;
ChemSpider	178524 ;
UNII	W1MKM70WQI;
KEGG	D05091 ;
ChEMBL	ChEMBL557580 ;
CompTox Dashboard (EPA)	DTXSID9057719 ;
Chemical and physical data
Formula	C29H28N2O7
Molar mass	516.550 g·mol−1
3D model (JSmol)	Interactive image;
	SMILES CC1=C(N=C(O1)C2=CC=CC=C2)CCOC3=CC=C(C=C3)CN(CC(=O)O)C(=O)OC4=CC=C(C=C4)OC;
	InChI InChI=1S/C29H28N2O7/c1-20-26(30-28(37-20)22-6-4-3-5-7-22)16-17-36-24-10-8-21(9-11-24)18-31(19-27(32)33)29(34)38-25-14-12-23(35-2)13-15-25/h3-15H,16-19H2,1-2H3,(H,32,33) ; Key:IRLWJILLXJGJTD-UHFFFAOYSA-N ;
	(what is this?) (verify)

Muraglitazar (proposed tradename Pargluva) is a dual peroxisome proliferator-activated receptor agonist with affinity to PPARα and PPARγ.^[1]

The drug had completed phase III clinical trials,^[2] however in May 2006 Bristol-Myers Squibb announced that it had discontinued further development.^[3]

Data on muraglitazar is relatively sparse due to the brief introduction and subsequent abandonment of this agent. One double-blind randomized clinical trial^[2] comparing muraglitazar and pioglitazone found that the effects of the former were favourable in terms of HDL-C increase, decrease in total cholesterol, apolipoprotein B, triglycerides and a greater reduction in HbA_1c (p <0.0001 for all comparisons). However, the muraglitazar group had a higher all-cause mortality, greater incidence of edema and heart failure and more weight gain compared to the pioglitazone group. A meta-analysis of the phase II and III clinical trials of muraglitazar revealed that it was associated with a greater incidence of myocardial infarction, stroke, transient ischemic attacks and congestive heart failure (CHF) when compared to placebo or pioglitazone.^[4]

By calling attention to adverse events made public through the FDA advisory committee process, Dr Nissen came upon a mechanism to steer FDA from the outside.^{[citation needed]} This mechanism came to fruition with rosiglitazone (Avandia) and led to FDA requiring demonstration of cardiac safety for new drugs to treat type 2 diabetes.^{[citation needed]} This process is described by Dr Robert Misbin in INSULIN-History from an FDA Insider, published June 1, 2020 on Amazon.^[promotion?]

References

^ Waites CR, Dominick MA, Sanderson TP, Schilling BE (November 2007). "Nonclinical safety evaluation of muraglitazar, a novel PPARalpha/gamma agonist". Toxicological Sciences. 100 (1): 248–58. doi:10.1093/toxsci/kfm193. PMID 17675651.
^ ^a ^b Kendall DM, Rubin CJ, Mohideen P, Ledeine JM, Belder R, Gross J, et al. (May 2006). "Improvement of glycemic control, triglycerides, and HDL cholesterol levels with muraglitazar, a dual (alpha/gamma) peroxisome proliferator-activated receptor activator, in patients with type 2 diabetes inadequately controlled with metformin monotherapy: A double-blind, randomized, pioglitazone-comparative study" (PDF). Diabetes Care. 29 (5): 1016–23. doi:10.2337/diacare.2951016. PMID 16644631.
^ "Bristol-Myers Squibb Announces Discontinuation of Development of Muraglitazar, an Investigational Oral Treatment for Type 2 Diabetes". PR Newswire from Bristol-Myers Squibb. May 18, 2006. Retrieved 9 November 2016.
^ Nissen SE, Wolski K, Topol EJ (November 2005). "Effect of muraglitazar on death and major adverse cardiovascular events in patients with type 2 diabetes mellitus". JAMA. 294 (20): 2581–6. doi:10.1001/jama.294.20.joc50147. PMID 16239637.

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[1] Waites CR, Dominick MA, Sanderson TP, Schilling BE (November 2007). "Nonclinical safety evaluation of muraglitazar, a novel PPARalpha/gamma agonist". Toxicological Sciences. 100 (1): 248–58. doi:10.1093/toxsci/kfm193. PMID 17675651.

[Kendall-2] Kendall DM, Rubin CJ, Mohideen P, Ledeine JM, Belder R, Gross J, et al. (May 2006). "Improvement of glycemic control, triglycerides, and HDL cholesterol levels with muraglitazar, a dual (alpha/gamma) peroxisome proliferator-activated receptor activator, in patients with type 2 diabetes inadequately controlled with metformin monotherapy: A double-blind, randomized, pioglitazone-comparative study" (PDF). Diabetes Care. 29 (5): 1016–23. doi:10.2337/diacare.2951016. PMID 16644631.

[3] "Bristol-Myers Squibb Announces Discontinuation of Development of Muraglitazar, an Investigational Oral Treatment for Type 2 Diabetes". PR Newswire from Bristol-Myers Squibb. May 18, 2006. Retrieved 9 November 2016.

[4] Nissen SE, Wolski K, Topol EJ (November 2005). "Effect of muraglitazar on death and major adverse cardiovascular events in patients with type 2 diabetes mellitus". JAMA. 294 (20): 2581–6. doi:10.1001/jama.294.20.joc50147. PMID 16239637.

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