Quinazolinone Derivatives as Orally Available Ghrelin Receptor Antagonists for the Treatment of Diabetes and Obesity

Rudolph, Joachim; Esler, William P.; O'Connor, Stephen E.; Coish, Philip; Wickens, Philip L.; Brands, Michael; Bierer, Donald; Bloomquist, Brian T.; Bondar, Georgiy; Chen, Libing; Chuang, Chih-Yuan; Claus, Thomas H.; Fathi, Zahra; Fu, Wenlang; Khire, Uday R.; Kristie, James; Liu, Xiao-Gao; Lowe, Derek; McClure, Andrea; Michels, Martin; Ortiz, Astrid; Ramsden, Philip; Schoenleber, Robert; Shelekhin, Tatiana E.; Vakalopoulos, Alexandros; Tang, Weifeng; Wang, Lei; Yi, Lin; Gardell, Stephen J.; Livingston, James N.; Sweet, Laurel J.; Bullock, William H.

doi:10.1021/jm070071+

Cited by 147 publications

(118 citation statements)

References 46 publications

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“…Therefore, GHS-R antagonists are expected to perform antiobesity functions by suppressing food intake and weight gain. In fact, small-molecule GHS-R antagonists and [D-Lys-3]-GHRP-6, which is one of the few known peptide antagonists of GHS-R, decrease food intake and weight gain via peripheral administration (7)(8)(9)(10).…”

mentioning

confidence: 99%

In vitro selection of a peptide antagonist of growth hormone secretagogue receptor using cDNA display

Ueno

Yoshida

Mondal

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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G protein-coupled receptors (GPCRs) are major drug targets, and their ligands are currently being explored and developed by many pharmaceutical companies and independent researchers. Class A (rhodopsin-like) GPCRs compose a predominant GPCR family; therefore, class A GPCR ligands are in demand. Growth hormone secretagogue receptor (GHS-R) is a class A GPCR that stimulates food intake by binding to its peptide ligand, ghrelin. Therefore, antagonists of GHS-R are expected to exert antiobesity function. In this article, we describe the use of cDNA display to screen for successfully and identify an antagonistic peptide of GHS-R. The antagonistic peptide inhibited the ghrelin-induced increase in intracellular Ca 2þ in vitro (IC 50 ¼ approximately 10 μM) and repressed the contraction of isolated animal stomach in response to ghrelin. Furthermore, peripheral administration of the peptide inhibited the food intake of mice. This work provides new insight into the development of antiobesity drugs and describes a method for the discovery of unique peptide ligands for class A GPCRs.aptamer | in vitro display | peptide drug | ligand screening | cell-based selection

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mentioning

confidence: 99%

In vitro selection of a peptide antagonist of growth hormone secretagogue receptor using cDNA display

Ueno

Yoshida

Mondal

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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“…A number of orally available GHS-R1a antagonists have also been developed, the most promising of which have been shown in rodents to cause reductions in food intake and body weight and to improve glucose tolerance [206,207]. However, a viable treatment for human obesity has yet to emerge from any of these strategies.…”

Section: Ghrelinmentioning

confidence: 99%

Obesity treatment: novel peripheral targets

Field¹,

Chaudhri²,

Bloom³

2009

Brit J Clinical Pharma

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Our knowledge of the complex mechanisms underlying energy homeostasis has expanded enormously in recent years. Food intake and body weight are tightly regulated by the hypothalamus, brainstem and reward circuits, on the basis both of cognitive inputs and of diverse humoral and neuronal signals of nutritional status. Several gut hormones, including cholecystokinin, glucagon-like peptide-1, peptide YY, oxyntomodulin, amylin, pancreatic polypeptide and ghrelin, have been shown to play an important role in regulating short-term food intake. These hormones therefore represent potential targets in the development of novel anti-obesity drugs. This review focuses on the role of gut hormones in short-and long-term regulation of food intake, and on the current state of development of gut hormone-based obesity therapies.

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“…Through its action on growth hormone secretagogue receptor type 1a, ghrelin exerts a variety of metabolic functions including stimulation of growth hormone release, stimulation of appetite and weight gain, and suppression of insulin secretion in rodents and humans (Nakazato et al, 2001;Wren et al, 2001;Dezaki et al, 2008;Cardona Cano et al, 2012;Heppner et al, 2012). Thus, antagonizing growth hormone secretagogue receptor (GHSR)-1a with small molecule antagonists or inverse agonists is anticipated to improve glucose homeostasis and insulin sensitivity, while eliciting beneficial effects on body weight (Serby et al, 2006;Esler et al, 2007;Rudolph et al, 2007;Soares et al, 2008;Costantino and Barlocco, 2009).…”

Section: Introductionmentioning

confidence: 99%

Reactive Metabolite Trapping Studies on Imidazo- and 2-Methylimidazo[2,1-b]thiazole-Based Inverse Agonists of the Ghrelin Receptor

et al. 2013

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The current study examined the bioactivation potential of ghrelin receptor inverse agonists, 1-{2-[2-chloro-4-(2H-1,2,3-triazol-2-yl)benzyl]-2,7-diazaspiro[3.5]nonan-7-yl}-2-(imidazo[2,1-b]thiazol-6-yl)ethanone (1) and 1-{2-[2-chloro-4-(2H-1,2,3-triazol-2-yl)benzyl]-2,7-diazaspiro[3.5]nonan-7-yl}-2-(2-methylimidazo[2,1-b]thiazol-6-yl) ethanone (2), containing a fused imidazo[2,1-b]thiazole motif in the core structure. Both compounds underwent oxidative metabolism in NADPH-and glutathione-supplemented human liver microsomes to yield glutathione conjugates, which was consistent with their bioactivation to reactive species. Mass spectral fragmentation and NMR analysis indicated that the site of attachment of the glutathionyl moiety in the thiol conjugates was on the thiazole ring within the bicycle. Two glutathione conjugates were discerned with the imidazo[2,1-b]thiazole derivative 1. One adduct was derived from the Michael addition of glutathione to a putative S-oxide metabolite of 1, whereas, the second adduct was formed via the reaction of a second glutathione molecule with the initial glutathione-S-oxide adduct. In the case of the 2-methylimidazo[2,1-b]thiazole analog 2, glutathione conjugation occurred via an oxidative desulfation mechanism, possibly involving thiazole ring epoxidation as the rate-limiting step. Additional insights into the mechanism were obtained via 18 O exchange and trapping studies with potassium cyanide. The mechanistic insights into the bioactivation pathways of 1 and 2 allowed the deployment of a rational chemical intervention strategy that involved replacement of the thiazole ring with a 1,2,4-thiadiazole group to yield 2-,4]thiadiazol-6-yl)ethanone (3). These structural changes not only abrogated the bioactivation liability but also retained the attractive pharmacological attributes of the prototype agents.

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Quinazolinone Derivatives as Orally Available Ghrelin Receptor Antagonists for the Treatment of Diabetes and Obesity

Cited by 147 publications

References 46 publications

In vitro selection of a peptide antagonist of growth hormone secretagogue receptor using cDNA display

In vitro selection of a peptide antagonist of growth hormone secretagogue receptor using cDNA display

Obesity treatment: novel peripheral targets

Reactive Metabolite Trapping Studies on Imidazo- and 2-Methylimidazo[2,1-b]thiazole-Based Inverse Agonists of the Ghrelin Receptor

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