Discovery and Characterization of Aminopiperidinecoumarin Melanin Concentrating Hormone Receptor 1 Antagonists

Kym, Philip R.; Iyengar, Rajesh; Souers, Andrew J.; Lynch, John K.; Judd, Andrew S.; Gao, Ju; Freeman, Jennifer C.; Mulhern, Mathew M.; Zhao, Gang; Vasudevan, Anil; Wódka, Dariusz; Blackburn, Christopher; Brown, J.; Lee, Jennifer; Cullis, Courtney; Lai, Su jen; LaMarche, Matthew J.; Marsilje, Tom; Roses, Jon; Sells, Todd B.; Geddes, Brad J.; Govek, Elizabeth; Patane, Michael A.; Fry, Dennis G.; Dayton, Brian D.; Brodjian, Sevan; Falls, Doug; Brune, Michael E.; Bush, Eugene N.; Shapiro, Robin; Knourek-Segel, Victoria; Fey, Thomas A.; McDowell, C. A.; Reinhart, Glenn A.; Preusser, Lee C.; Marsh, Kennan C.; Hernandez, Lisa E.; Sham, Hing L.; Collins, Christine A.

doi:10.1021/jm050598r

Cited by 46 publications

(25 citation statements)

References 13 publications

(24 reference statements)

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“…The Abbott group has disclosed a comprehensive series of reports that highlight a number of features in numerous chemical series and detail the optimization of compound potency, safety and selectivity in obese rodent models Vasudevan et al, 2004;Souers et al, 2005a,b;Vasudevan et al, 2005;Kym et al, 2005;Lynch et al, 2006;Iyengar et al, 2007). After describing early leads that included substituted quinolines Vasudevan et al, 2004) and indazoles , they seem to have settled in on an aminopiperidine chromone series (Fig.…”

Section: Development Of Small Molecule Mchr1 Antagonistsmentioning

confidence: 99%

Anti-obesity effects of small molecule melanin-concentrating hormone receptor1 (MCHR1) antagonists

Luthin

2007

Life Sciences

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Section: Development Of Small Molecule Mchr1 Antagonistsmentioning

confidence: 99%

Anti-obesity effects of small molecule melanin-concentrating hormone receptor1 (MCHR1) antagonists

Luthin

2007

Life Sciences

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“…Over the past few years, antagonism of the MCH1R has been a popular target for pharmacological treatment of obesity (Vasudevan et al, 2004;Kym et al, 2005;Morens et al, 2005;Palani et al, 2005a,b;Kim et al, 2006;. These reports describe various chemical scaffolds with both in vitro and in vivo activity, without definition of where the critical site of action is located.…”

Section: Discussionmentioning

confidence: 99%

Small-Molecule Melanin-Concentrating Hormone-1 Receptor Antagonists Require Brain Penetration for Inhibition of Food Intake and Reduction in Body Weight

Wos

Dowty

et al. 2007

J Pharmacol Exp Ther

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The melanin-concentrating hormone-1 receptor (MCH1R) is a G-protein-coupled receptor expressed in the brain and peripheral tissues that regulates energy storage and body weight. Here, we focused on discovery of the mechanism and site of action for a small-molecule MCH1R antagonist, which yields weight loss in a mouse model of human obesity. MCH1R is expressed throughout the brain but also found in peripheral tissues known to regulate fat storage and utilization, e.g., skeletal muscle and adipose tissue. Previous studies of MCH1R antagonist studies have not delineated the site that is critical for mediating the anorexigenic and weight-reducing actions. In this study, we evaluated the role of the brain and peripheral tissue receptors. We developed a novel nonbrain-permeable MCH antagonist analog with a carboxylic acid moiety to specifically test the site of action. Based on in vitro and in vivo assays, the analog is not able to cross the blood-brain barrier and does not lead to inhibition of food intake and reduced body weight. The data clearly demonstrate that MCH1R antagonists need access to the brain to reduce body weight and fat mass. The brainpermeable MCH1R antagonist leads to significant reduction in body weight and fat mass in diet-induced obese mice. The effect is dose-dependent and appears to be partially driven by a reduction in food intake. Finally, these studies show the utility of a medicinal chemistry approach to address an important biological and pharmacological question.The obesity epidemic continues to increase in many developed and developing countries (Ogden et al., 2003;Haslam and James, 2005). The 2004 National Health and Nutrition Examination Survey indicated that more than 50% of the United States population is either obese or overweight (Hedley et al., 2004;Ogden et al., 2006). More importantly, the incidence of obese and overweight children is also on the rise. Obesity is associated with multiple metabolic disorders, including diabetes and cardiovascular disease (Ogden et al., 2003). There is a great interest in identifying behavioral and pharmacological approaches to reduce body weight in obese and overweight individuals.Weight loss intervention strategies include targets for reducing hunger/appetite, enhancing satiety, increasing metabolism/ energy utilization, blocking fat absorption, inhibiting adipose tissue differentiation, and inducing adipose tissue apoptosis. The current therapeutic approaches for weight loss include diet, exercise, and pharmacotherapy. Efficacy is very modest, with a high rate of recidivism at the end of the treatment period (Schnee et al., 2006). Orlistat (Xenical) and sibutramine (Meridia) are currently the only two approved pharmacotherapy agents on the market. Orlistat blocks absorption of fat from the intestine, whereas sibutramine reduces appetite by acting on brain pathways that regulate hunger (Bray and Ryan, 2007). These drugs show limited efficacy, and considerable attention is focused on the development of new reagents to decrease body weight.

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“…1‐Methylindol‐6‐yl(phenyl)methanone (4da): The starting material, 1‐methylindole‐6‐carbaldehyde ( 2d ), was prepared according to the reported method 18. Purification through silica gel column chromatography (hexane/AcOEt, 5:1) gave 4da (191 mg, 0.81 mmol, 81 % yield) as a pale brown solid; m.p.…”

Section: Methodsmentioning

confidence: 99%

One‐Pot Synthesis of Heteroaryl and Diheteroaryl Ketones through Palladium‐Catalyzed 1,2‐Addition and Oxidation

et al. 2013

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A synthetic method was developed for the preparation of heteroaryl and diheteroaryl ketones from aldehydes and organoboronic acids through a palladium‐catalyzed 1,2‐addition and oxidation that uses an aryl iodide as the oxidant. This one‐pot process shows high tolerance for a broad range of heterocyclic substrates by using 1.0–3.0 mol‐% of the catalyst that is formed from allylpalladium chloride dimer and a thioether‐imidazolinium chloride. In addition to fine‐tuning the catalytic system, the use of a sterically hindered aryl iodide that has a substituent at the ortho position, such as 2‐iodotoluene, is important to obtain the desired ketones with heterocyclic moieties in good to excellent yields.

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Discovery and Characterization of Aminopiperidinecoumarin Melanin Concentrating Hormone Receptor 1 Antagonists

Cited by 46 publications

References 13 publications

Anti-obesity effects of small molecule melanin-concentrating hormone receptor1 (MCHR1) antagonists

Anti-obesity effects of small molecule melanin-concentrating hormone receptor1 (MCHR1) antagonists

Small-Molecule Melanin-Concentrating Hormone-1 Receptor Antagonists Require Brain Penetration for Inhibition of Food Intake and Reduction in Body Weight

One‐Pot Synthesis of Heteroaryl and Diheteroaryl Ketones through Palladium‐Catalyzed 1,2‐Addition and Oxidation

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