Discovery of highly potent and efficacious MC4R agonists with spiroindane N-Me-1,2,4-triazole privileged structures for the treatment of obesity

He, Shuwen; Ye, Zhixiong; Dobbelaar, Peter H.; Bakshi, Raman K.; Hong, Qingmei; Dellureficio, James; Sebhat, Iyassu K.; Guo, Liangqin; Liu, Jian; Jian, Tianying; Lai, Yingjie; Franklin, Christopher L.; Reibarkh, Mikhail; Holmes, Mark A.; Weinberg, David H.; MacNeil, Tanya; Tang, Rui; Tamvakopoulos, Constantin; Peng, Qianping; Miller, Randy R.; Stearns, Ralph A.; Chen, Howard Y.; Chen, Airu S.; Strack, Alison M.; Fong, Tung M.; Wyvratt, Matthew J.; Nargund, Ravi P.

doi:10.1016/j.bmcl.2010.09.049

Cited by 19 publications

(17 citation statements)

References 30 publications

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“…Acyl amidines as important active building blocks have frequently appeared in biomolecules, and recently they have been found with ability to construct nitrogenous heterocycles [162]. The facile, practical and efficient one-pot reaction of acyl amidine 109 with hydrazine hydrate reliably provided potent PI3K inhibitor 110 with a special structure of thiophene triazole, but the reaction mechanism was not mentioned (Scheme 44) [163].…”

Section: Cyclizations Of Hydrazinesmentioning

confidence: 99%

Current Developments in the Syntheses of 1,2,4-Triazole Compounds

Zhang¹,

Damu²,

Cai³

et al. 2014

COC

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Heterocyclic 1,2,4-triazole derivatives possess unusually spacious potentiality as medicinal agents, agricultural chemicals, functional materials, ionic liquids, supramolecular catalysts as well as artificial enzymes and receptors for supramolecular recognition and biomimetic catalysis, and their various researches and developments have been being a quite rapidly developing and active highlight topic with an infinite space. Numerous efforts have been directed toward various types of possible applications of 1,2,4-triazole-based compounds and a lot of important progress has been made, especially their preparations have attracted increasing attention. This review systematically summarized the recent advances in the syntheses of 1,2,4-triazole derivatives, including: (1) Cyclizations to form triazole ring; (2) Transformations of heterocyclic compounds to construct triazole ring; (3) Substitutions on 1,2,4-triazole ring; (4) Structural modifications in side chains of 1,2,4-triazole ring. It was hoped that this review would be helpful for the design and development of highly efficient preparation of 1,2,4-triazole derivatives with various sorts and varieties of extensively potential applications in medicine, agriculture, chemistry, materials, supramolecular sciences and so on.

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Section: Cyclizations Of Hydrazinesmentioning

confidence: 99%

Current Developments in the Syntheses of 1,2,4-Triazole Compounds

Zhang¹,

Damu²,

Cai³

et al. 2014

COC

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“…The concept of developing MC4R agonists for the treatment of obesity has been around for more than a decade, and agonists have been shown to have efficacy in rodent models of obesity (23). However, despite strenuous efforts, no compounds have reached clinical trials for the treatment of obesity.…”

Section: Obesity Is An Increasingly Important Global Health Problem Tmentioning

confidence: 99%

“…Comparison of the structure of kB1(GHFRWG;23-28) with the native kalata B1 framework indicates that the overall fold is maintained. The cyclic cystine knot motif and ␤-hairpin are the defining structural features of the cyclotides, and both are present in kB1(GHFRWG; [23][24][25][26][27][28], despite the sequence changes in loop 6. The introduction of non-native sequences into the CCK scaffold can sometimes lead to disordered loops (45,48).…”

Section: Design Synthesis and Characterization Of The Graftedmentioning

confidence: 99%

“…5b, and it was of interest to determine how their presence might influence the nature of the molecular surface. Analysis of the surface of kB1(GHFRWG; [23][24][25][26][27][28] shows that a group of surface-exposed hydrophobic residues is punctated by polar or charged residues. In addition, the arginine in loop 6 is highly solvent-exposed.…”

Section: Design Synthesis and Characterization Of The Graftedmentioning

confidence: 99%

“…Three-dimensional Structure of kB1(GHFRWG; [23][24][25][26][27][28]-Given the potency and selectivity observed for kB1(GHFRWG;23-28), its three-dimensional structure was determined to provide insight into structure-activity relationships. Structures were determined using torsion angle dynamics in the program CYANA, and the 20 structures with the lowest target function were chosen to represent the global fold.…”

Section: Design Synthesis and Characterization Of The Graftedmentioning

confidence: 99%

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Design, Synthesis, Structural and Functional Characterization of Novel Melanocortin Agonists Based on the Cyclotide Kalata B1

Eliasen

Daly

Wulff

et al. 2012

Journal of Biological Chemistry

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Background: Cyclotides are useful scaffolds to stabilize bioactive peptides. Results: Four melanocortin analogues of kalata B1 were synthesized. One is a selective MC4R agonist. Conclusion:The analogues retain the native kalata B1 scaffold and introduce a designed pharmacological activity, validating cyclotides as protein engineering scaffolds. Significance: A novel type of melanocortin agonist has been developed, with potential as a drug lead for treating obesity.

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Spiropiperidines

2018

Privileged Structures in Drug Discovery

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Discovery of highly potent and efficacious MC4R agonists with spiroindane N-Me-1,2,4-triazole privileged structures for the treatment of obesity

Cited by 19 publications

References 30 publications

Current Developments in the Syntheses of 1,2,4-Triazole Compounds

Current Developments in the Syntheses of 1,2,4-Triazole Compounds

Design, Synthesis, Structural and Functional Characterization of Novel Melanocortin Agonists Based on the Cyclotide Kalata B1

Spiropiperidines

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