Potent, orally absorbed glucagon receptor antagonists

Laszlo, Stephen E. de; Hacker, Candice; Li, Bing; Kim, Dooseop; MacCoss, Malcolm; Mantlo, Nathan B.; Pivnichny, James V.; Colwell, Larry; Koch, Gregory; Cascieri, Margaret A.; Hagmann, William K.

doi:10.1016/s0960-894x(99)00081-5

Cited by 168 publications

(89 citation statements)

References 13 publications

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“…Preliminary data indicate that these compounds are absorbed systemically after oral administration (11), suggesting that they have the potential to be useful, orally active hypoglycemic agents. The prototype of this class, L-168,049, is a high affinity, noncompetitive antagonist of the human glucagon receptor, which inhibits glucagon-stimulated adenylyl cyclase with a K b of 25 nM.…”

Section: Discussionmentioning

confidence: 99%

“…However, there have been no subsequent reports in the patent or scientific literature describing the development of potent antagonists from this series. Our initial screening efforts identified a series of triarylimidazole and triarylpyrrole compounds with significant binding affinity for the human glucagon receptor, and efforts to evaluate the structure-activity relationships of this series have lead to the identification of potent glucagon antagonists (11). In the present article, we describe the identification and characterization of a potent glucagon antagonist from this series.…”

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confidence: 99%

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Characterization of a Novel, Non-peptidyl Antagonist of the Human Glucagon Receptor

Cascieri¹,

Koch²,

Ber³

et al. 1999

Journal of Biological Chemistry

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Glucagon is a 29-amino acid peptide that is an important counter-regulatory hormone in the control of glucose homeostasis (1). Glucagon secretion from the endocrine pancreas induces an increase in hepatic glycogenolysis and gluconeogenesis, and it attenuates the ability of insulin to inhibit these processes. As such, the overall rates of hepatic glucose synthesis and glycogen metabolism are controlled by the systemic ratio of insulin and glucagon (2, 3). Therefore, glucagon antagonists have the potential to improve hepatic insulin sensitivity and to be effective hypoglycemic agents.Peptidyl glucagon antagonists and their hypoglycemic activity were first described over 15 years ago, and an extensive exploration of the structure/activity relationships of these glucagon analogs has been reported (4 -6). The hepatic receptor for glucagon was cloned recently (7,8), confirming that it is a member of the seven-transmembrane domain, G-protein-coupled receptor superfamily. This receptor superfamily has a binding pocket for small-molecule ligands within the transmembrane domain that has made it possible to identify nonpeptidyl antagonists for many receptor families in which the endogenous ligands are small peptides or proteins (9). Thus, we initiated an effort to identify non-peptidyl, orally active antagonists for the human glucagon receptor.Collins et al. (10) have described a dichloroquinoxaline glucagon antagonist with weak affinity (IC 50 ϭ 4 M) for the rat glucagon receptor. However, there have been no subsequent reports in the patent or scientific literature describing the development of potent antagonists from this series. Our initial screening efforts identified a series of triarylimidazole and triarylpyrrole compounds with significant binding affinity for the human glucagon receptor, and efforts to evaluate the structure-activity relationships of this series have lead to the identification of potent glucagon antagonists (11). In the present article, we describe the identification and characterization of a potent glucagon antagonist from this series. MATERIALS AND METHODSCharacterization of Binding Affinity and Functional Activity-Stable CHO 1 cell lines or COS cells transiently expressing the human glucagon receptor were prepared as described previously (8, 12). Antagonist binding affinity was assessed by measuring inhibition of radiolabeled glucagon binding to CHO cell membranes. Briefly, 125 I-glucagon (58 pM) binding to the membrane preparation was measured in 20 mM Tris, pH 7.4, containing 1 mM dithiothreitol, 5 g/ml leupeptin, 10 g/ml benzamidine, 40 g/ml bacitracin, 5 g/ml soybean trypsin inhibitor, and 3 M o-phenanthroline Ϯ 1 M glucagon for 1 h at room temperature. Bound cpm were recovered by filtration using a Tomtec harvester and quantified in a ␥-scintillation counter.The ability of compound to inhibit glucagon-stimulated adenylyl cyclase was assessed as described previously (12). Briefly, cells were harvested from monolayers with enzyme-free cell dissociation solution (Specialty Media, Inc.) and were...

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Section: Discussionmentioning

confidence: 99%

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confidence: 99%

Characterization of a Novel, Non-peptidyl Antagonist of the Human Glucagon Receptor

Cascieri¹,

Koch²,

Ber³

et al. 1999

Journal of Biological Chemistry

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“…The immunoneutralization of the endogenous glucagon, administration of glucagon receptor antagonists, reduction of glucagon receptor expression or the deletion of glucagon receptors leads to a reduction of hyperglycemia in diabetic animal models (Brand et al, 1994;Liang et al, 2004;Gelling et al, 2003). Given the potential for SST to inhibit glucagon secretion it has been considered as adjunct therapy with insulin to treat diabetes (de Laszlo et al, 1999;Petersen and Sullivan 2001;Madsen et al, 2002).…”

Section: Somatostatin In Therapy Of Diabetes Mellitusmentioning

confidence: 99%

Function and expression of somatostatin receptors of the endocrine pancreas

Strowski

Blake

2008

Molecular and Cellular Endocrinology

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“…1,2 The imidazoles and their derivatives are very important molecules because many applications in chemical processes, especially in pharmaceuticals. 3,4 Various substituted imidazoles act as inhibitors of p38 MAP kinase, 5 B-Raf kinase, 6 glucagon receptors, 7 plant growth regulators, 8 antitumor 9 and pesticides. 10 There are many methods for the synthesis of polysubstituted imidazoles such as condensation of diones, aldehydes, primary amines and ammonia in the presence of various acid catalysts, [11][12][13] N-alkylation of trisubstituted imidazoles, 14 condensation of benzil or benzoin acetate with aldehydes, primary amines and ammonia in the presence of copper acetate 15,16 etc.…”

Section: Introductionmentioning

confidence: 99%

Facile and Rapid Synthesis of Polysubstituted Imidazoles by Employing Y(NO3)3×6H2O as Catalyst

2012

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Abstract. An efficient and environmentally adapted synthesis of polysubstituted imidazoles in one-pot and multicomponent reaction of various aldehydes, benzil, aliphatic and aromatic primary amines and ammonium acetate under solvent-free condition is reported. Highly efficient role of Y(NO 3 ) 3 × 6H 2 O as catalyst in this synthesis was shown. By this advantage, several polysubstituted imidazoles as pharmaceutical important molecules can be prepared in high yield and high purity. This method is very easy and rapid for the synthesis of imidazole derivatives. All products were deduced from their IR and NMR spectroscopic and elemental analysis data. The catalyst exhibited remarkable reusable activity. (doi: 10.5562/cca1979)

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Potent, orally absorbed glucagon receptor antagonists

Cited by 168 publications

References 13 publications

Characterization of a Novel, Non-peptidyl Antagonist of the Human Glucagon Receptor

Characterization of a Novel, Non-peptidyl Antagonist of the Human Glucagon Receptor

Function and expression of somatostatin receptors of the endocrine pancreas

Facile and Rapid Synthesis of Polysubstituted Imidazoles by Employing Y(NO3)3×6H2O as Catalyst

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