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Research ArticleArticle

Demonstration of the Innate Electrophilicity of 4-(3-(Benzyloxy)phenyl)-2-(ethylsulfinyl)-6-(trifluoromethyl)pyrimidine (BETP), a Small-Molecule Positive Allosteric Modulator of the Glucagon-Like Peptide-1 Receptor

Heather Eng, Raman Sharma, Thomas S. McDonald, David J. Edmonds, Jean-Philippe Fortin, Xianping Li, Benjamin D. Stevens, David A. Griffith, Chris Limberakis, Whitney M. Nolte, David A. Price, Margaret Jackson and Amit S. Kalgutkar
Drug Metabolism and Disposition August 2013, 41 (8) 1470-1479; DOI: https://doi.org/10.1124/dmd.113.052183
Heather Eng
Pharmacokinetics, Dynamics and Metabolism–New Chemical Entities, Groton, Connecticut (H.E., R.S., T.S.M.) and Cambridge, Massachusetts (A.S.K.); Cardiovascular, Metabolic and Endocrine Diseases Medicinal Chemistry, Cambridge (D.J.E., B.D.S., D.A.G., W.M.N., D.A.P.) and Groton (C.L.); and Cardiovascular, Metabolic and Endocrine Diseases Research Unit, Cambridge (J.-P.F., X.L., M.J.) Pfizer, Inc.
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Raman Sharma
Pharmacokinetics, Dynamics and Metabolism–New Chemical Entities, Groton, Connecticut (H.E., R.S., T.S.M.) and Cambridge, Massachusetts (A.S.K.); Cardiovascular, Metabolic and Endocrine Diseases Medicinal Chemistry, Cambridge (D.J.E., B.D.S., D.A.G., W.M.N., D.A.P.) and Groton (C.L.); and Cardiovascular, Metabolic and Endocrine Diseases Research Unit, Cambridge (J.-P.F., X.L., M.J.) Pfizer, Inc.
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Thomas S. McDonald
Pharmacokinetics, Dynamics and Metabolism–New Chemical Entities, Groton, Connecticut (H.E., R.S., T.S.M.) and Cambridge, Massachusetts (A.S.K.); Cardiovascular, Metabolic and Endocrine Diseases Medicinal Chemistry, Cambridge (D.J.E., B.D.S., D.A.G., W.M.N., D.A.P.) and Groton (C.L.); and Cardiovascular, Metabolic and Endocrine Diseases Research Unit, Cambridge (J.-P.F., X.L., M.J.) Pfizer, Inc.
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David J. Edmonds
Pharmacokinetics, Dynamics and Metabolism–New Chemical Entities, Groton, Connecticut (H.E., R.S., T.S.M.) and Cambridge, Massachusetts (A.S.K.); Cardiovascular, Metabolic and Endocrine Diseases Medicinal Chemistry, Cambridge (D.J.E., B.D.S., D.A.G., W.M.N., D.A.P.) and Groton (C.L.); and Cardiovascular, Metabolic and Endocrine Diseases Research Unit, Cambridge (J.-P.F., X.L., M.J.) Pfizer, Inc.
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Jean-Philippe Fortin
Pharmacokinetics, Dynamics and Metabolism–New Chemical Entities, Groton, Connecticut (H.E., R.S., T.S.M.) and Cambridge, Massachusetts (A.S.K.); Cardiovascular, Metabolic and Endocrine Diseases Medicinal Chemistry, Cambridge (D.J.E., B.D.S., D.A.G., W.M.N., D.A.P.) and Groton (C.L.); and Cardiovascular, Metabolic and Endocrine Diseases Research Unit, Cambridge (J.-P.F., X.L., M.J.) Pfizer, Inc.
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Xianping Li
Pharmacokinetics, Dynamics and Metabolism–New Chemical Entities, Groton, Connecticut (H.E., R.S., T.S.M.) and Cambridge, Massachusetts (A.S.K.); Cardiovascular, Metabolic and Endocrine Diseases Medicinal Chemistry, Cambridge (D.J.E., B.D.S., D.A.G., W.M.N., D.A.P.) and Groton (C.L.); and Cardiovascular, Metabolic and Endocrine Diseases Research Unit, Cambridge (J.-P.F., X.L., M.J.) Pfizer, Inc.
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Benjamin D. Stevens
Pharmacokinetics, Dynamics and Metabolism–New Chemical Entities, Groton, Connecticut (H.E., R.S., T.S.M.) and Cambridge, Massachusetts (A.S.K.); Cardiovascular, Metabolic and Endocrine Diseases Medicinal Chemistry, Cambridge (D.J.E., B.D.S., D.A.G., W.M.N., D.A.P.) and Groton (C.L.); and Cardiovascular, Metabolic and Endocrine Diseases Research Unit, Cambridge (J.-P.F., X.L., M.J.) Pfizer, Inc.
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David A. Griffith
Pharmacokinetics, Dynamics and Metabolism–New Chemical Entities, Groton, Connecticut (H.E., R.S., T.S.M.) and Cambridge, Massachusetts (A.S.K.); Cardiovascular, Metabolic and Endocrine Diseases Medicinal Chemistry, Cambridge (D.J.E., B.D.S., D.A.G., W.M.N., D.A.P.) and Groton (C.L.); and Cardiovascular, Metabolic and Endocrine Diseases Research Unit, Cambridge (J.-P.F., X.L., M.J.) Pfizer, Inc.
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Chris Limberakis
Pharmacokinetics, Dynamics and Metabolism–New Chemical Entities, Groton, Connecticut (H.E., R.S., T.S.M.) and Cambridge, Massachusetts (A.S.K.); Cardiovascular, Metabolic and Endocrine Diseases Medicinal Chemistry, Cambridge (D.J.E., B.D.S., D.A.G., W.M.N., D.A.P.) and Groton (C.L.); and Cardiovascular, Metabolic and Endocrine Diseases Research Unit, Cambridge (J.-P.F., X.L., M.J.) Pfizer, Inc.
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Whitney M. Nolte
Pharmacokinetics, Dynamics and Metabolism–New Chemical Entities, Groton, Connecticut (H.E., R.S., T.S.M.) and Cambridge, Massachusetts (A.S.K.); Cardiovascular, Metabolic and Endocrine Diseases Medicinal Chemistry, Cambridge (D.J.E., B.D.S., D.A.G., W.M.N., D.A.P.) and Groton (C.L.); and Cardiovascular, Metabolic and Endocrine Diseases Research Unit, Cambridge (J.-P.F., X.L., M.J.) Pfizer, Inc.
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David A. Price
Pharmacokinetics, Dynamics and Metabolism–New Chemical Entities, Groton, Connecticut (H.E., R.S., T.S.M.) and Cambridge, Massachusetts (A.S.K.); Cardiovascular, Metabolic and Endocrine Diseases Medicinal Chemistry, Cambridge (D.J.E., B.D.S., D.A.G., W.M.N., D.A.P.) and Groton (C.L.); and Cardiovascular, Metabolic and Endocrine Diseases Research Unit, Cambridge (J.-P.F., X.L., M.J.) Pfizer, Inc.
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Margaret Jackson
Pharmacokinetics, Dynamics and Metabolism–New Chemical Entities, Groton, Connecticut (H.E., R.S., T.S.M.) and Cambridge, Massachusetts (A.S.K.); Cardiovascular, Metabolic and Endocrine Diseases Medicinal Chemistry, Cambridge (D.J.E., B.D.S., D.A.G., W.M.N., D.A.P.) and Groton (C.L.); and Cardiovascular, Metabolic and Endocrine Diseases Research Unit, Cambridge (J.-P.F., X.L., M.J.) Pfizer, Inc.
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Amit S. Kalgutkar
Pharmacokinetics, Dynamics and Metabolism–New Chemical Entities, Groton, Connecticut (H.E., R.S., T.S.M.) and Cambridge, Massachusetts (A.S.K.); Cardiovascular, Metabolic and Endocrine Diseases Medicinal Chemistry, Cambridge (D.J.E., B.D.S., D.A.G., W.M.N., D.A.P.) and Groton (C.L.); and Cardiovascular, Metabolic and Endocrine Diseases Research Unit, Cambridge (J.-P.F., X.L., M.J.) Pfizer, Inc.
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Abstract

4-(3-(Benzyloxy)phenyl)-2-(ethylsulfinyl)-6-(trifluoromethyl)pyrimidine (BETP) represents a novel small-molecule activator of the glucagon-like peptide-1 receptor (GLP-1R), and exhibits glucose-dependent insulin secretion in rats following i.v. (but not oral) administration. To explore the quantitative pharmacology associated with GLP-1R agonism in preclinical species, the in vivo pharmacokinetics of BETP were examined in rats after i.v. and oral dosing. Failure to detect BETP in circulation after oral administration of a 10-mg/kg dose in rats was consistent with the lack of an insulinotropic effect of orally administered BETP in this species. Likewise, systemic concentrations of BETP in the rat upon i.v. administration (1 mg/kg) were minimal (and sporadic). In vitro incubations in bovine serum albumin, plasma, and liver microsomes from rodents and humans indicated a facile degradation of BETP. Failure to detect metabolites in plasma and liver microsomal incubations in the absence of NADP was suggestive of a covalent interaction between BETP and a protein amino acid residue(s) in these matrices. Incubations of BETP with glutathione (GSH) in buffer revealed a rapid nucleophilic displacement of the ethylsulfoxide functionality by GSH to yield adduct M1, which indicated that BETP was intrinsically electrophilic. The structure of M1 was unambiguously identified by comparison of its chromatographic and mass spectral properties with an authentic standard. The GSH conjugate of BETP was also characterized in NADPH- and GSH-supplemented liver microsomes and in plasma samples from the pharmacokinetic studies. Unlike BETP, M1 was inactive as an allosteric modulator of the GLP-1R.

Footnotes

    • Received March 28, 2013.
    • Accepted May 7, 2013.
  • dx.doi.org/10.1124/dmd.113.052183.

  • Copyright © 2013 by The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 41 (8)
Drug Metabolism and Disposition
Vol. 41, Issue 8
1 Aug 2013
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Demonstration of the Innate Electrophilicity of 4-(3-(Benzyloxy)phenyl)-2-(ethylsulfinyl)-6-(trifluoromethyl)pyrimidine (BETP), a Small-Molecule Positive Allosteric Modulator of the Glucagon-Like Peptide-1 Receptor
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Research ArticleArticle

Intrinsic Electrophilicity of BETP

Heather Eng, Raman Sharma, Thomas S. McDonald, David J. Edmonds, Jean-Philippe Fortin, Xianping Li, Benjamin D. Stevens, David A. Griffith, Chris Limberakis, Whitney M. Nolte, David A. Price, Margaret Jackson and Amit S. Kalgutkar
Drug Metabolism and Disposition August 1, 2013, 41 (8) 1470-1479; DOI: https://doi.org/10.1124/dmd.113.052183

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Research ArticleArticle

Intrinsic Electrophilicity of BETP

Heather Eng, Raman Sharma, Thomas S. McDonald, David J. Edmonds, Jean-Philippe Fortin, Xianping Li, Benjamin D. Stevens, David A. Griffith, Chris Limberakis, Whitney M. Nolte, David A. Price, Margaret Jackson and Amit S. Kalgutkar
Drug Metabolism and Disposition August 1, 2013, 41 (8) 1470-1479; DOI: https://doi.org/10.1124/dmd.113.052183
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