Optimization of 3-(1<i>H</i>-Indazol-3-ylmethyl)-1,5-benzodiazepines as Potent, Orally Active CCK-A Agonists

Henke, Brad R.; Aquino, Christopher; Birkemo, Larry S.; Croom, Dallas K.; Dougherty, R. W.; Ervin, Gregory N.; Grizzle, Mary K.; Hirst, Gavin C.; James, M K; Johnson, Michael F.; Queen, Kennedy L.; Sherrill, Ronald G.; Sugg, Elizabeth E.; Suh, Edward M.; Szewczyk, Jerzy W.; Unwalla, Rayomand J.; Yingling, Jeff; Willson, Timothy M.

doi:10.1021/jm970265x

Cited by 85 publications

(30 citation statements)

References 45 publications

(75 reference statements)

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“…Ligand structure-activity relationship data indicate that the N1 substituent confers agonism, with an isopropyl group being optimal for full agonist activity (4,24). In the type 1 CCK receptor agonist model, this substituent pointed toward a hydrophobic part of the pocket near TM7.…”

Section: Cck2 Receptors With Substitution Of Cck1 Receptor Tm Segmentsmentioning

confidence: 99%

Molecular Basis for Benzodiazepine Agonist Action at the Type 1 Cholecystokinin Receptor

Harikumar

Cawston

Lam

et al. 2013

Journal of Biological Chemistry

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Background: Cholecystokinin receptor type 1 (CCK1R) stimulates satiety. Results: Binding and activity of a CCK1R agonist/CCK2R antagonist are studied at wild-type and chimeric receptors, and ligand-guided model refinement is utilized. Conclusion:The small molecule agonist docking site is distinct from the antagonist site, with benzodiazepines docked with consistent pose, including approximation with Leu 7.39 . Significance: The molecular model and determinants for small molecule agonist action should facilitate drug development.

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Section: Cck2 Receptors With Substitution Of Cck1 Receptor Tm Segmentsmentioning

confidence: 99%

Molecular Basis for Benzodiazepine Agonist Action at the Type 1 Cholecystokinin Receptor

Harikumar

Cawston

Lam

et al. 2013

Journal of Biological Chemistry

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“…47 This, too, was used in a ligand-directed computational effort to generalize our understanding of the active conformation of this pocket. 43 It also provided molecular insights into the determinants of biological activity, with evidence for a key interaction between a 'trigger functionality' within a benzodiazepine agonist and the receptor residues it likely interacts with.…”

Section: Characterization Of the Small-molecule Ligand-binding Pocketmentioning

confidence: 99%

Cholecystokinin-induced satiety, a key gut servomechanism that is affected by the membrane microenvironment of this receptor

et al. 2016

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The gastrointestinal (GI) tract has a central role in nutritional homeostasis, as location for food ingestion, digestion and absorption, with the gut endocrine system responding to and regulating these events, as well as influencing appetite. One key GI hormone with the full spectrum of these activities is cholecystokinin (CCK), a peptide released from neuroendocrine I cells scattered through the proximal intestine in response to fat and protein, with effects to stimulate gall bladder contraction and pancreatic exocrine secretion, to regulate gastric emptying and intestinal transit, and to induce satiety. There has been interest in targeting the type 1 CCK receptor (CCK1R) for drug development to provide non-caloric satiation as an aid to dieting and weight loss; however, there have been concerns about CCK1R agonists related to side effects and potential trophic impact on the pancreas. A positive allosteric modulator (PAM) of CCK action at this receptor without intrinsic agonist activity could provide a safer and more effective approach to long-term administration. In addition, CCK1R stimulus-activity coupling has been shown to be negatively affected by excess membrane cholesterol, a condition described in the metabolic syndrome, thereby potentially interfering with an important servomechanism regulating appetite. A PAM targeting this receptor could also potentially correct the negative impact of cholesterol on CCK1R function. We will review the molecular basis for binding natural peptide agonist, binding and action of small molecules within the allosteric pocket, and the impact of cholesterol. Novel strategies for taking advantage of this receptor for the prevention and management of obesity will be reviewed.International Journal of Obesity Supplements (2016) 6, S22-S27; doi:10.1038/ijosup.2016.5 INTRODUCTIONThe prevalence of obesity has been progressively increasing throughout the United States and around the world, contributing to a parallel increase in the prevalence of type 2 diabetes mellitus and its associated comorbidities. 1 These problems have been responsible for extraordinary morbidity, suffering, loss in productivity and premature mortality. In spite of major efforts to develop effective weight reduction diets, diet aids, medications, medical devices and surgical procedures, the trajectory for this continues in the wrong direction. Bariatric surgery has proven to be quite effective in patients with morbid obesity; 2 however, this is quite expensive and not scalable, certainly not keeping up with the increasing prevalence of the most severe end of this clinical continuum. The activity of acute dieting and exercise has been similarly effective in inducing weight loss; however, it has not been durable, with an extremely high incidence of regaining weight to or even beyond the starting point. After a long hiatus in approved drugs, three new diet medications have recently been approved, 3-5 but all carry concerns about safety, and there are requirements for registration and careful clinical follow-up, re...

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“…For the treatment of obesity, Henke from Glaxo Wellcome has optimized a series of 3-(1H-indazol-3-ylmethyl)-1,5-benzodiazepines -potent and orally active CCK-A agonists derived from 31 [64]. Steroidal pyrazoles have long been known.…”

Section: Mesmentioning

confidence: 99%

Five‐Membered Heterocycles: 1,2‐Azoles. Part 1. Pyrazoles

Elguero

Silva

Tomé

2011

Modern Heterocyclic Chemistry

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Optimization of 3-(1H-Indazol-3-ylmethyl)-1,5-benzodiazepines as Potent, Orally Active CCK-A Agonists

Cited by 85 publications

References 45 publications

Molecular Basis for Benzodiazepine Agonist Action at the Type 1 Cholecystokinin Receptor

Molecular Basis for Benzodiazepine Agonist Action at the Type 1 Cholecystokinin Receptor

Cholecystokinin-induced satiety, a key gut servomechanism that is affected by the membrane microenvironment of this receptor

Five‐Membered Heterocycles: 1,2‐Azoles. Part 1. Pyrazoles

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