Small-molecule glucagon receptor antagonists

Ling, Anthony

doi:10.1358/dof.2002.027.10.701362

Cited by 19 publications

(6 citation statements)

References 10 publications

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“…There have been many reports detailing efforts to identify a small molecule glucagon receptor antagonist (GRA) as a potential oral treatment for type 2 diabetes, and much of the earlier work was reviewed by DeMong in 2008. Early examples of GRA scaffolds such as a tetrasubstituted quinoxaline, catechole derivatives, a triaryl imidazole, a phenol-containing alkylidene hydrazide, , and a tetrasubstituted thiophene have not been followed up with further reports.…”

Section: Introductionmentioning

confidence: 99%

Discovery of a Novel Glucagon Receptor Antagonist N-[(4-{(1S)-1-[3-(3, 5-Dichlorophenyl)-5-(6-methoxynaphthalen-2-yl)-1H-pyrazol-1-yl]ethyl}phenyl)carbonyl]-β-alanine (MK-0893) for the Treatment of Type II Diabetes

et al. 2012

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A potent, selective glucagon receptor antagonist 9m, N-[(4-{(1S)-1-[3-(3,5-dichlorophenyl)-5-(6-methoxynaphthalen-2-yl)-1H-pyrazol-1-yl]ethyl}phenyl)carbonyl]-β-alanine, was discovered by optimization of a previously identified lead. Compound 9m is a reversible and competitive antagonist with high binding affinity (IC(50) of 6.6 nM) and functional cAMP activity (IC(50) of 15.7 nM). It is selective for glucagon receptor relative to other family B GPCRs, showing IC(50) values of 1020 nM for GIPR, 9200 nM for PAC1, and >10000 nM for GLP-1R, VPAC1, and VPAC2. Compound 9m blunted glucagon-induced glucose elevation in hGCGR mice and rhesus monkeys. It also lowered ambient glucose levels in both acute and chronic mouse models: in hGCGR ob/ob mice it reduced glucose (AUC 0-6 h) by 32% and 39% at 3 and 10 mpk single doses, respectively. In hGCGR mice on a high fat diet, compound 9m at 3, and 10 mpk po in feed lowered blood glucose levels by 89% and 94% at day 10, respectively, relative to the difference between the vehicle control and lean hGCGR mice. On the basis of its favorable biological and DMPK properties, compound 9m (MK-0893) was selected for further preclinical and clinical evaluations.

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Section: Introductionmentioning

confidence: 99%

Discovery of a Novel Glucagon Receptor Antagonist N-[(4-{(1S)-1-[3-(3, 5-Dichlorophenyl)-5-(6-methoxynaphthalen-2-yl)-1H-pyrazol-1-yl]ethyl}phenyl)carbonyl]-β-alanine (MK-0893) for the Treatment of Type II Diabetes

et al. 2012

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“…In the H N region of the HMBC, all 14 sequential C‘ i −H N i+1 correlations (excluding the four prolines and the N-terminus) could be observed (plus one intraresidue C‘ i −H N i cross-peak of Ser 8 ). For three proline H α resonances (all except Pro), a weak correlation to the preceding carbonyl was observed. The carbonyl carbons of the Asp 9 and Asn 14 side chains could be identified by correlations to the H β andfor Asn 14 also the side chain amide resonances.…”

Section: Resultsmentioning

confidence: 96%

“…Several publications disclose peptidic and nonpeptidic glucagon receptor antagonists. , Among natural products, cephalochromin has been described as a glucagon receptor antagonist . Therefore we used it as a reference compound.…”

Section: Resultsmentioning

confidence: 99%

BI-32169, a Bicyclic 19-Peptide with Strong Glucagon Receptor Antagonist Activity from Streptomyces sp.

et al. 2004

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A new bicyclic 19-peptide, BI-32169, has been isolated from the culture broth of Streptomyces sp. (DSM 14996). Its structure has been established by amino acid analysis, mass spectrometry, and 2D NMR analysis. BI-32169 consists exclusively of protein amino acids and is cyclized from the side chain of Asp(9) to the N-terminus of Gly(1). One disulfide bond between Cys(6) and Cys(19) forms a bicyclic structure. BI-32169 and its methyl ester derivative showed potent inhibitory activity against the human glucagon receptor (IC(50) 440 and 320 nM, respectively) in a functional cell-based assay.

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“…This follows previously published reviews of the GCGRA chemical matter [17,20], including several reviews of the patent literature [21][22][23]. The most recent patent review published in 2010.…”

Section: Patent Reviewsmentioning

confidence: 91%