Discovery of a piperazine urea based compound as a potent, selective, orally bioavailable melanocortin subtype-4 receptor partial agonist

Hong, Qingmei; Bakshi, Raman K.; Palucki, Brenda L.; Park, Min K.; Ye, Zhixiong; He, Shuwen; Pollard, Patrick G.; Sebhat, Iyassu K.; Liu, Jian; Guo, Liangqin; Cashen, Doreen E.; Martin, William J.; Weinberg, David H.; MacNeil, Tanya; Tang, Rui; Tamvakopoulos, Constantin; Peng, Qianping; Miller, Randy R.; Stearns, Ralph A.; Chen, Howard Y.; Chen, Airu S.; Strack, Alison M.; Fong, Tung M.; MacIntyre, D. Euan; Wyvratt, Matthew J.; Nargund, Ravi P.

doi:10.1016/j.bmcl.2011.02.090

Cited by 17 publications

(14 citation statements)

References 31 publications

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“…33 Several other small molecules have been reported from the Merck Research Laboratories including a report on a piperazine urea based MC4R partial agonist with nM potency at the human MC4R, but without an effect on erectile activity in the rodents. 41 A focused urea-based non-peptide agonist library has previously been reported by our lab. 34 Compound CGJ-7 was identified in that study as selective for the mMC3R (4.4 µM) as compared to the mMC4R, which showed no agonist activity up to 100 µM.…”

Section: Resultsmentioning

confidence: 99%

“…40 An orally bioavailable piperazine urea based compound (a selective MC4R partial agonist) has been reported to modulate food intake in animal models without any effect on erectile activity. 41 An earlier study of a “focused” library based on the core tri-peptide sequence, “Phe-Trp-Lys” that included a urea linkage resulted in identification of lead compounds CGJ-7 and CGJ-9 (Figure 2). 34 Notably, compound CGJ-9 , containing the 1,2,3,4-tetrahydroisoquinoline (TIQ) functionality displayed full agonist activity at both the mMC3R and mMC4Rs.…”

Section: Introductionmentioning

confidence: 99%

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Synthesis and Structure–Activity Relationships of Substituted Urea Derivatives on Mouse Melanocortin Receptors

Singh

Kast

Dirain

et al. 2015

ACS Chem. Neurosci.

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The melanocortin system is involved in the regulation of several complex physiological functions. In particular, the melanocortin- 3 and −4 receptors (MC3R/MC4R) have been demonstrated to regulate body weight, energy homeostasis, and feeding behavior. Synthetic and endogenous melanocortin agonists have been shown to be anorexigenic in rodent models. Herein, we report synthesis and structure-activity relationship (SAR) studies of 27 non-peptide small molecule ligands based on an unsymmetrical substituted urea core. Three templates containing key residues from the lead compounds, showing diversity at three positions (R1, R2, R3), were designed and synthesized. The syntheses were optimized for efficient microwave-assisted chemistry that significantly reduced total syntheses time compared to a previously reported room temperature method. The pharmacological characterization of the compounds on the mouse melanocortin receptors identified compounds 1 and 12 with full agonist activity at the mMC4R, but no activity was observed at the mMC3R when tested up to 100 µM concentrations. The SAR identified compounds possessing aliphatic or saturated cyclic amines at the R1 position, bulky aromatic groups at the R2 position, and benzyl group at the R3 position resulted in mMC4R selectivity over the mMC3R. The small molecule template and SAR knowledge from this series may be helpful in further design of MC3R/MC4R selective small molecule ligands.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Synthesis and Structure–Activity Relationships of Substituted Urea Derivatives on Mouse Melanocortin Receptors

Singh

Kast

Dirain

et al. 2015

ACS Chem. Neurosci.

View full text Add to dashboard Cite

show abstract

“…Compound 137 was the most potent compound, both in terms of binding and functional activity [235]. Among the various piperazine analogues developed by Hong et al, compound 138 displayed potent anti-obesity activity [236].…”

Section: Antiobesity Activitymentioning

confidence: 99%

Piperazine scaffold: A remarkable tool in generation of diverse pharmacological agents

Shaquiquzzaman

Verma

Marella

et al. 2015

European Journal of Medicinal Chemistry

187

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“…A major disadvantage of most MC4R agonists is their poor bioavailability. A piperazine-based highly specific partial MC4R agonist has been shown to have good oral bioavailability in rat (Hong et al, 2011). It reduces food intake by almost 40%.…”

Section: Anti-obesity Drugs In Pipelinementioning

confidence: 99%

New targets to treat obesity and the metabolic syndrome

Martin

Mani

2015

European Journal of Pharmacology

102

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Metabolic syndrome (MetS) is a cluster of associated metabolic traits that collectively confer unsurpassed risk for development of cardiovascular disease (CVD) and type 2 diabetes compared to any single CVD risk factor. Truncal obesity plays an exceptionally critical role among all metabolic traits of the MetS. Consequently, the prevalence of the MetS has steadily increased with the growing epidemics of obesity. Pharmacotherapy has been available for obesity for more than one decade, but with little success in improving the metabolic profiles. The serotonergic drugs and inhibitors of pancreatic lipases were among the few drugs that were initially approved to treat obesity. At the present time, only the pancreatic lipase inhibitor orlistat is approved for long-term treatment of obesity. New classes of anti-diabetic drugs, including glucagon-like peptide 1 receptor (GLP-1R) agonists and Dipeptidyl-peptidase IV (DPP-IV) inhibitors, are currently being evaluated for their effects on obesity and metabolic traits. The genetic studies of obesity and metabolic syndrome have identified novel molecules acting on the hunger and satiety peptidergic signaling of the gut-hypothalamus axis or the melanocortin system of the brain and are promising targets for future drug development. The goal is to develop drugs that not only treat obesity, but also favorably impact its associated traits.

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Discovery of a piperazine urea based compound as a potent, selective, orally bioavailable melanocortin subtype-4 receptor partial agonist

Cited by 17 publications

References 31 publications

Synthesis and Structure–Activity Relationships of Substituted Urea Derivatives on Mouse Melanocortin Receptors

Synthesis and Structure–Activity Relationships of Substituted Urea Derivatives on Mouse Melanocortin Receptors

Piperazine scaffold: A remarkable tool in generation of diverse pharmacological agents

New targets to treat obesity and the metabolic syndrome

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