Discovery of (2S)-N-[(1R)-2-[4-cyclohexyl-4-[[(1,1-dimethylethyl)amino]carbonyl]-1-piperidinyl]-1-[(4-fluorophenyl)methyl]-2-oxoethyl]-4-methyl-2-piperazinecarboxamide (MB243), a potent and selective melanocortin subtype-4 receptor agonist

Palucki, Brenda L.; Park, Min K.; Nargund, Ravi P.; Ye, Zhixiong; Sebhat, Iyassu K.; Pollard, Patrick G.; Kalyani, Rubana N.; Tang, Rui; MacNeil, Tanya; Weinberg, David H.; Vongs, Aurawan; Rosenblum, Charles; Doss, George A.; Miller, Randall R.; Stearns, Ralph A.; Peng, Qianping; Tamvakopoulos, Constantin; McGowan, Erin; Martin, William J.; Metzger, Joseph M.; Shepherd, Cherrie; Strack, Alison M.; MacIntyre, D. Euan; Ploeg, Lex H.T. Van der; Patchett, Arthur A.

doi:10.1016/j.bmcl.2004.10.020

Cited by 41 publications

(23 citation statements)

References 33 publications

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“…Comparing the structures of His-DPhe-Arg-Trp and THIQ (Figure 3), it may be observed that the His is replaced with a constrained tetrahydroisoquinoline moiety in THIQ , DPhe by a 4-chlorophenyl ring, and the Trp may be in close proximity to the triazole heterocycle. Later modifications by Merck included replacing the 4-chlorophenyl with a 4-fluorophenyl to improve potency at the hMC4R, and potentially minimizing off-target effects by replacing the triazole with a t -butylamide group and substituting the tetrahydroisoquinoline moiety with a piperazine ring (MB243, Figure 3) [145]. Another key contribution from the Merck group was the discovery of the t -butylpyrrolidine containing MC4R-selective ligands (including MK0493, Figure 3) [146], a scaffold that is evident in many of the molecules presently reviewed.…”

Section: Small Molecule Ligandsmentioning

confidence: 99%

Bench-top to clinical therapies: A review of melanocortin ligands from 1954 to 2016

Ericson

Lensing

Fleming

et al. 2017

Biochimica et Biophysica Acta (BBA) - Molecular Basis of Diseas

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The discovery of the endogenous melanocortin agonists in the 1950s have resulted in sixty years of melanocortin ligand research. Early efforts involved truncations or select modifications of the naturally occurring agonists leading to the development of many potent and selective ligands. With the identification and cloning of the five known melanocortin receptors, many ligands were improved upon through bench-top in vitro assays. Optimization of select properties resulted in ligands adopted as clinical candidates. A summary of every melanocortin ligand is outside the scope of this review. Instead, this review will focus on the following topics: classic melanocortin ligands, selective ligands, small molecule (non-peptide) ligands, ligands with sex-specific effects, bivalent and multivalent ligands, and ligands advanced to clinical trials. Each topic area will be summarized with current references to update the melanocortin field on recent progress.

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Section: Small Molecule Ligandsmentioning

confidence: 99%

Bench-top to clinical therapies: A review of melanocortin ligands from 1954 to 2016

Ericson

Lensing

Fleming

et al. 2017

Biochimica et Biophysica Acta (BBA) - Molecular Basis of Diseas

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“…Very recently, Ye and coworkers (Merck) have reported [116] the use of isoquinuclidines, in 38 (RY-764) [116], as a replacement for the piperazine residue of 39 [117] (Fig. 13) to attenuate oxidative metabolism and subsequent binding to liver microsomal proteins.…”

Section: Melanocortin-4 (Mc4) Receptor Agonistsmentioning

confidence: 99%

“…This modification enhanced in vivo efficacy of the series. The compound 39 was prepared [116,117] in a linear fashion as shown in Scheme 3. This compound 38 was the most promising one in the series.…”

Section: Melanocortin-4 (Mc4) Receptor Agonistsmentioning

confidence: 99%

Antiobesity Therapy: Emerging Drugs and Targets

Das

Chakrabarti²

2006

CMC

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Obesity and its associated morbidities and mortalities are the effects of imbalance between energy intake and expenditure. The healthcare burden for the treatment of obesity is significantly high, due to increased risk of secondary chronic diseases such as hypertension and associated co-morbidities such as diabetes and cardiovascular disease. Lack of physical activity, high fat diets and sedentary life styles are major factors contributing to obesity. However, genetic predisposition and ethnicity are increasingly found to cause obesity. Till date, approved therapeutics have addressed excess energy intake by acting on central neural circuits that regulate feeding or on peripheral mechanisms to reduce nutrient absorption from the gut. These approaches have met with moderate success; and recently with safety concerns, leaving an unmet medical need for effective and safe pharmacotherapy for obesity thereby posing a significant challenge to pharmaceutical industry. Potential antiobesity drugs, which are being investigated by different companies, can be classified in 4 broad categories: 1) Agents that primarily decrease appetite through central action; 2) Agents that primarily increase metabolic rate or affect metabolism through peripheral action; 3) Agents that act on gastrointestinal tract; and 4) Agents that not only affect obesity but also overall Metabolic Syndrome. The current review will deal mainly with different molecules, which are under development for the above-mentioned targets and also their potential benefits and disadvantages.

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“…In recent year, the pursuit of small molecule and selective agonists of the hMC4R has been intensified and numerous nonpeptide agonists and antagonists have been developed (19, 32, 34–43). THIQ is a selective agonist for MC4R (39) (Figure 1). Previously, Pogozheva et al reported that THIQ shares some binding sites with NDP-MSH at hMC4R using hypothesis-driven selection of receptor amino acid residue for site-directed mutagenesis study (32).…”

Section: Introductionmentioning

confidence: 99%

Key amino acid residues in the melanocortin-4 receptor for nonpeptide THIQ specific binding and signaling

Yang

Cai

Chen

et al. 2009

Regulatory Peptides

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Melanocortin 4 receptor (MC4R) plays an important role in the regulation of food intake and glucose homeostasis. Synthetic nonpeptide compound N- (3R)-1 4-tetrahydroisoquinolinium-3-ylcarbonyl -(1R)-1-(4-chlorobenzyl)-2- 4-cyclohexyl-4-(1H-1,2,4-triazol-1-ylmethyl)piperidin-1-yl -2-oxoethylamine (THIQ) is a potent agonist at MC4R but not at hMC2R. In this study, we utilized two approaches (chimeric receptor and site-directed mutagenesis) to narrow down the key amino acid residues of MC4R responsible for THIQ binding and signaling. Cassette substitutions of the second, third, fourth, fifth, and sixth transmembrane regions (TMs) of the human MC4R (hMC4R) with the homologous regions of hMC2R were constructed. Our results indicate that the cassette substitutions of these TMs of the hMC4R with homologous regions of the hMC2R did not significantly alter THIQ binding affinity and potency except the substitution of the hMC4R TM3, suggesting that the conserved amino acid residues in these TMs of the hMC4R are main potential candidates for THIQ binding and signaling while non conserved residues in TM3 of MC4R may also be involved. Nineteen MC4R mutants were then created, including 13 conserved amino acid residues and 6 non-conserved amino acid residues. Our results indicate that seven conserved residue [E100 (TM2), D122 (TM3), D126 (TM3), F254 (TM6), W258 (TM6), F261 (TM6), H264 (TM6)] are important for THIQ binding and three non-conserved residues [N123 (TM3), I129 (TM3) and S131 (TM3)] are involved in THIQ selectivity. In conclusion, our results suggest that THIQ utilize both conserved and non-conserved amino acid residues for binding and signaling at hMC4R and non conserved residues may be responsible for MC4R selectivity.

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Discovery of (2S)-N-[(1R)-2-[4-cyclohexyl-4-[[(1,1-dimethylethyl)amino]carbonyl]-1-piperidinyl]-1-[(4-fluorophenyl)methyl]-2-oxoethyl]-4-methyl-2-piperazinecarboxamide (MB243), a potent and selective melanocortin subtype-4 receptor agonist

Cited by 41 publications

References 33 publications

Bench-top to clinical therapies: A review of melanocortin ligands from 1954 to 2016

Bench-top to clinical therapies: A review of melanocortin ligands from 1954 to 2016

Antiobesity Therapy: Emerging Drugs and Targets

Key amino acid residues in the melanocortin-4 receptor for nonpeptide THIQ specific binding and signaling

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