Design and syntheses of melanocortin subtype-4 receptor agonists: evolution of the pyridazinone archetype

Ujjainwalla, Feroze; Warner, Daniel; Walsh, Thomas; Wyvratt, Matthew J.; Zhou, Changyou; Lu, Yang; Kalyani, Rubana N.; MacNeil, Tanya; Ploeg, Lex H.T. Van der; Rosenblum, Charles; Tang, Rui; Vongs, Aurawan; Weinberg, David H.; Goulet, Mark T.

doi:10.1016/j.bmcl.2003.09.026

Cited by 32 publications

(21 citation statements)

References 15 publications

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“…The second distinct structural series developed as a result of HTS screening was reported by our laboratories in 2003 [42]. Unreported SAR studies developed an early screening hit to pyridazinone 47 which demonstrated modest hMC4 receptor binding and functional activity (Fig.…”

Section: (2) Pyridazinonesmentioning

confidence: 95%

Small Molecule Ligands of the Human Melanocortin-4 Receptor

Ujjainwalla¹,

Sebhat

2007

CTMC

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Genetic and pharmacological studies, involving both animals and humans, suggest that the central MC4 receptor plays a key role in homeostatic control, most probably via regulation of appetite and energy expenditure. This has stimulated intense research efforts in the field of drug discovery to identify MC4 receptor agonists and antagonists for the therapeutic treatment of obesity and diseases associated with loss of body weight. This article constitutes a near comprehensive review of the published scientific literature on small molecule ligands of the hMC4 receptor since 2002.

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Section: (2) Pyridazinonesmentioning

confidence: 95%

Small Molecule Ligands of the Human Melanocortin-4 Receptor

Ujjainwalla¹,

Sebhat

2007

CTMC

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“…These derivatives were claimed for the treatment of obesity, diabetes, cancer, inflammation and Alzheimer's diseases. Merck has also disclosed [112] the design and syntheses of new MC4 receptor agonists based on structural motifs other than piperidine and piperazine moieties. A…”

Section: Selective 5-ht 2c 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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“…4 Selective agonists of the human MC 4 R are of potential use for the treatment of obesity, diabetes and sexual dysfunctions. 5 Peptide/ protein ligands display drawbacks, such as enzymatic instability and failure to cross the blood-brain barrier, and should preferably be replaced by non-peptide substances, which are better suited for application as drugs. 6 Several non-peptide MC 4 R selective compounds have recently been found.…”

Section: Introductionmentioning

confidence: 99%

A non‐peptide radioiodinated high affinity melanocortin‐4 receptor ligand

Mutulis

Yahorava

Mutule

et al. 2003

Labelled Comp Radiopharmac

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Summary4-Cyclohexyl-4-[(1,2,4-triazol-1-yl)methyl]piperidine was introduced into stepwise peptide synthesis procedures using Boc chemistry and derivatives of d-4-iodophenylalanine and d-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid. A halogen replacement analogue (I-Mex2) of a known high affinity melanocortin-4 receptor selective compound resulted. It showed a subnanomolar affinity when evaluated on the melanocortin-4 receptor in competition with the a-MSH peptide analogue 125 I-NDP-MSH. By treatment with hexamethylditin and tetrakis(triphenylphosphine) palladium I-Mex2 was converted to the corresponding trimethylstannyl derivative. In the next step, Na 125 I was oxidized by an iodobead. Iododestannylation proceeded in the presence of 1 M phosphate buffer, pH 2.5, and the radioactive derivative 125 I-Mex2 formed was separated by HPLC at 40% radiochemical yield. Preliminary investigation showed that 125 I-Mex2

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Design and syntheses of melanocortin subtype-4 receptor agonists: evolution of the pyridazinone archetype

Cited by 32 publications

References 15 publications

Small Molecule Ligands of the Human Melanocortin-4 Receptor

Small Molecule Ligands of the Human Melanocortin-4 Receptor

Antiobesity Therapy: Emerging Drugs and Targets

A non‐peptide radioiodinated high affinity melanocortin‐4 receptor ligand

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