Discovery and pharmacology of the covalent GLP-1 receptor (GLP-1R) allosteric modulator BETP: A novel tool to probe GLP-1R pharmacology.

Allosteric Regulation / drug effects Amino Acid Sequence Animals Cyclic AMP / metabolism Drug Discovery Glucagon-Like Peptide-1 Receptor / agonists Humans Pyrimidines / chemistry Small Molecule Libraries / pharmacology
Agonist Allosteric modulator BETP Class B GPCR Covalent Drug discovery G-protein coupled receptor Glucagon-like peptide 1 Insulin Transmembrane helix

Journal

Advances in pharmacology (San Diego, Calif.)
ISSN: 1557-8925
Titre abrégé: Adv Pharmacol
Pays: United States
ID NLM: 9015397

Informations de publication

Date de publication:
2020
Historique:
entrez: 18 5 2020
pubmed: 18 5 2020
medline: 30 9 2020
Statut: ppublish

Résumé

The glucagon-like peptide-1 receptor (GLP-1R) is a significant therapeutic target for small molecule drug discovery given the therapeutic impact of peptide agonists in the diabetes sphere. We review the discovery and subsequent characterization of the small molecule GLP-1R allosteric modulator 4-(3-(Benzyloxy)phenyl)-2-(ethylsulfinyl)-6-(trifluoromethyl)pyrimidine (BETP). BETP is a covalent modulator of the GLP-1R, and we discuss the pharmacological implications and possible structural basis of this novel mode of action. We highlight the insights into class B G-protein coupled receptor pharmacology and biology provided by studies conducted with BETP. These include the descriptions of exquisite allosteric modulator probe dependence and biased signaling in vitro and in vivo. We conclude with an analysis of the utility of BETP as a chemical probe for the GLP-1R.

Identifiants

DOI: 10.1016/bs.apha.2020.02.001 PMID: 32416867
pubmed: 32416867
pii: S1054-3589(20)30004-1
doi: 10.1016/bs.apha.2020.02.001
pii:
doi:

Substances chimiques

4-(3-(benzyloxy)phenyl)-2-(ethylsulfinyl)-6-(trifluoromethyl)pyrimidine 0
Glucagon-Like Peptide-1 Receptor 0
Pyrimidines 0
Small Molecule Libraries 0
Cyclic AMP E0399OZS9N

Types de publication

Journal Article Review

Langues

eng

Sous-ensembles de citation

IM

Pagination

173-191

Informations de copyright

© 2020 Elsevier Inc. All rights reserved.

Déclaration de conflit d'intérêts

Conflict of interest All authors are employees of Eli Lilly and Company and may own company stock or possess stock options.

Auteurs

Francis S Willard (FS)

Quantitative Biology, Lilly Research Laboratories, Indianapolis, IN, United States. Electronic address: willardfs@lilly.com.

Joseph D Ho (JD)

Lilly Biotechnology Center, San Diego, CA, United States.

Kyle W Sloop (KW)

Diabetes and Complications, Lilly Research Laboratories, Indianapolis, IN, United States.

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Classifications MeSH

questionsmedicales.fr › Phénomènes chimiques › Phénomènes biochimiques › Régulation allostérique › Discovery and pharmacology of the covalent...
questionsmedicales.fr › Sciences de l'information › Sources d'information › Services d'information › Documentation › Données de séquences moléculaires › Séquence d'acides aminés › Discovery and pharmacology of the covalent...
questionsmedicales.fr › Eucaryotes › Animaux › Discovery and pharmacology of the covalent...
questionsmedicales.fr › Acides nucléiques, nucléotides et nucléosides › Nucléotides › Ribonucléotides › Nucléotides adényliques › AMP cyclique › Discovery and pharmacology of the covalent...
questionsmedicales.fr › Techniques d'investigation › Développement de médicament › Découverte de médicament › Discovery and pharmacology of the covalent...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Protéines membranaires › Récepteurs de surface cellulaire › Récepteurs peptidiques › Récepteur hormone gastrointestinale › Récepteurs des peptides similaires au glucagon › Récepteur du peptide-1 similaire au glucagon › Discovery and pharmacology of the covalent...
questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Primates › Haplorhini › Catarrhini › Hominidae › Humains › Discovery and pharmacology of the covalent...
questionsmedicales.fr › Composés hétérocycliques › Composés hétéromonocycliques › Pyrimidines › Discovery and pharmacology of the covalent...
questionsmedicales.fr › Actions chimiques et utilisations › Utilisations spécialisées de produits chimiques › Produits chimiques de laboratoire › Bibliothèques de petites molécules › Discovery and pharmacology of the covalent...