Discovery of N-benzyl-2-[(4S)-4-(1H-indol-3-ylmethyl)-5-oxo-1-phenyl-4,5-dihydro-6H-[1,2,4]triazolo[4,3-a][1,5]benzodiazepin-6-yl]-N-isopropylacetamide, an orally active, gut-selective CCK1 receptor agonist for the potential treatment of obesity

Elliott, Richard L.; Cameron, Kimberly O.; Chin, Janice E.; Bartlett, Jeremy A.; Beretta, Elena; Chen, Yue; Jardine, Paul Da Silva; Dubins, Jeffrey S.; Gillaspy, Melissa L.; Hargrove, Diane M.; Kalgutkar, Amit S.; LaFlamme, Janet A.; Lame, Mary E.; Martin, Kelly A.; Maurer, Tristan S.; Nardone, Nancy A.; Oliver, Robert M.; Scott, Dennis O.; Sun, Daxi; Swick, Andrew G.; Trebino, Catherine E.; Zhang, Yingxin

doi:10.1016/j.bmcl.2010.08.115

Cited by 25 publications

(21 citation statements)

References 23 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…As previously reported 8, 9 , both triazolobenzodiazepinones, CE-326597 and PF-04756956 (Fig. 1), were highly efficacious agonists, stimulating maximal intracellular calcium responses not statistically different from those elicited by CCK at the CCK1R (Fig.…”

Section: Resultssupporting

confidence: 81%

“…In an attempt to achieve this, the Pfizer group chose to take advantage of physicochemical properties of the molecules in their discovery series, seeking an appropriate balance of solubility and membrane permeability to result in adequate exposure of active drug to enteric neurons, and rapid hepatic clearance to minimize systemic exposure 8, 9 . They were also interested in low biliary clearance to allow prompt gallbladder relaxation, as occurs physiologically.…”

Section: Discussionmentioning

confidence: 99%

“…These molecules exhibited efficacy with no gastrointestinal side effects in pre-clinical rodent studies. A Phase 2 clinical trial of CE-326597 for 12 weeks in patients who were obese with type 2 diabetes mellitus did not achieve the desired endpoint 8 , and further clinical development was not pursued. While these ligands are not ideal drugs, they provide enough structural diversity from GI181771X and from each other to provide additional insights into the nature of allosteric agonist binding pose and into the determinants of activity.…”

Section: Discussionmentioning

confidence: 99%

“…Both compounds were evaluated by reversed-phase HPLC with UV detection at 215 nm, and were found to be greater than 95 percent pure. These ligands have been reported to act as full agonists at the CCK1R 8, 9 . Cholecystokinin octapeptide (CCK-26-33, based on the numbering of CCK-33; also known as CCK-8) was purchased from Peninsula Laboratories (Belmont, CA).…”

Section: Methodsmentioning

confidence: 99%

“…In the current work, we have taken advantage of two triazolobenzodiazepinone agonists that have been reported to be full agonists of the CCK1R 8, 9 . Their chemical structures are distinct from the 1,5-benzodiazepine that has had its docking studied in greatest detail previously 5 , and these ligands possess unique pharmacological properties worthy of further analysis.…”

mentioning

confidence: 99%

See 4 more Smart Citations

Molecular Mechanism of Action of Triazolobenzodiazepinone Agonists of the Type 1 Cholecystokinin Receptor. Possible Cooperativity across the Receptor Homodimeric Complex

et al. 2015

View full text Add to dashboard Cite

The type 1 cholecystokinin receptor (CCK1R) has multiple physiologic roles relating to nutrient homeostasis, including mediation of post-cibal satiety. This effect has been central in efforts to develop agonists of this receptor as part of a program to manage and/or prevent obesity. While a number of small molecule CCK1R agonists have been developed, none has yet been approved for clinical use, based on inadequate efficacy, side effects, or the potential for toxicity. Understanding the molecular details of docking and mechanism of action of these ligands can be helpful in the rational refinement and enhancement of small molecule drug candidates. In the current work, we have defined the mechanism of binding and activity of two triazolobenzodiazepinones, CE-326597 and PF-04756956, which are reported to be full agonist ligands. To achieve this, we utilized receptor binding with a series of allosteric and orthosteric radioligands at structurally-related CCK1R and CCK2R, as well as chimeric CCK1R/CCK2R constructs exchanging residues in the allosteric pocket, and assessment of biological activity. These triazolobenzodiazepinones docked within the intramembranous small molecule allosteric ligand pocket, with higher affinity binding to CCK2R than CCK1R, yet with biological activity exclusive to or greatly enhanced at CCK1R. These ligands exhibited cooperativity with benzodiazepine binding across the CCK1R homodimeric complex, resulting in their ability to inhibit only a fraction of the saturable binding of a benzodiazepine radioligand, unlike other small molecule antagonists and agonists of this receptor. This may contribute to the understanding of the unique short duration and reversible gallbladder contraction observed in vivo upon administration of these drugs.

show abstract

Section: Resultssupporting

confidence: 81%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

mentioning

confidence: 99%

See 3 more Smart Citations

Molecular Mechanism of Action of Triazolobenzodiazepinone Agonists of the Type 1 Cholecystokinin Receptor. Possible Cooperativity across the Receptor Homodimeric Complex

et al. 2015

View full text Add to dashboard Cite

show abstract

ChemInform Abstract: Discovery of N‐Benzyl‐2‐ [(4S)‐4‐(1H‐indol‐3‐ylmethyl)‐5‐oxo‐1‐phenyl‐4,5‐dihydro‐6H‐ [1,2,4]triazolo[4,3‐a][1,5]benzodiazepin‐6‐yl]‐N‐isopropylacetamide (I), an Orally Active, Gut‐Selective CCK1 Receptor Agonist for the Potential Treatment of Obesity.

Cameron

2011

ChemInform

View full text Add to dashboard Cite

Do we need anti‐obesity drugs?

Hainer

Hainerová

2012

Diabetes Metabolism Res

View full text Add to dashboard Cite

SummaryThe increasing global prevalence of obesity urgently requires an implementation of efficient preventive and therapeutic measures. Weight loss and its maintenance should be considered one of the most important strategies to reduce the incidence of obesity-related co-morbidities such as diabetes and cardiovascular diseases. Lifestyle modification focused on diet and physical activity represents the essential component of any kind of weight management. However, only an intensive lifestyle intervention can be efficient in terms of long-term weight loss. Anti-obesity drugs affect different targets in the central nervous system or peripheral tissues and improve regulatory and metabolic disturbances that contribute to the development of obesity. Antiobesity medications provide modest additional fat loss to that achieved by lifestyle modification alone, reduce visceral fat stores, improve programme adherence, weight loss maintenance, diminish obesity-related health risks and improve a quality of life. Anti-obesity drugs do play a role in weight management. Their replacement with placebo is followed by weight regain. Due to adverse events, several anti-obesity drugs were withdrawn from the market over the past few years and currently only orlistat remains available for long-term obesity management. Drug withdrawals, failure of clinical trials with several new anti-obesity compounds as well as inappropriate demands of drug regulating agencies concerning the study protocol led to scepticism about the perspectives in the pharmacotherapy of obesity. However, recently developed anti-obesity medications such as gut hormone analogues and drug combinations provided encouraging results in terms of weight loss, safety and improvement of cardio-metabolic health risks.

show abstract

Discovery of N-benzyl-2-[(4S)-4-(1H-indol-3-ylmethyl)-5-oxo-1-phenyl-4,5-dihydro-6H-[1,2,4]triazolo[4,3-a][1,5]benzodiazepin-6-yl]-N-isopropylacetamide, an orally active, gut-selective CCK1 receptor agonist for the potential treatment of obesity

Cited by 25 publications

References 23 publications

Molecular Mechanism of Action of Triazolobenzodiazepinone Agonists of the Type 1 Cholecystokinin Receptor. Possible Cooperativity across the Receptor Homodimeric Complex

Molecular Mechanism of Action of Triazolobenzodiazepinone Agonists of the Type 1 Cholecystokinin Receptor. Possible Cooperativity across the Receptor Homodimeric Complex

Do we need anti‐obesity drugs?

Contact Info

Product

Resources

About