Synthesis and Biological Studies of 2-aminothiophene Derivatives As Positive Allosteric Modulators of Glucagon-like Peptide 1 Receptor

Overview

Journal Bioorg Med Chem

Specialties Biochemistry
Chemistry

Date 2024 Aug 8

PMID 39116711

Authors

Jeffrey A Campbell

Phu Do

Zhiyu Li

Faisal Malik

Christopher Mead

Nick Miller

Christopher Pisiechko

Kimberly Powers

Zhijun Li

Affiliations

Soon will be listed here.

Abstract

As a step toward the development of novel small-molecule positive allosteric modulators (PAMs) of glucagon-like peptide 1 receptor (GLP-1R) for the treatment of type 2 diabetes, obesity, and heart diseases, we discovered a novel 2-amino-thiophene (2-AT) based lead compound bearing an ethyl 3-carboxylate appendage. In this work, we report the syntheses and biological studies of more than forty 2-AT analogs, that have revealed a 2-aminothiophene-3-arylketone analogue 7 (MW 299) showing approximately a 2-fold increase in insulin secretion at 5 μM when combined with the GLP-1 peptide at 10 nM. In vivo studies using CD1 mice at a dose of 10 mg/kg, clearly demonstrated that the blood plasma glucose level was lowered by 50% after 60 min. Co-treatment of 7 with sitagliptin, an inhibitor of GLP-1 degrading enzyme Dipeptidyl Peptidase IV, further confirmed 7 to be an effective PAM of GLP-1R. The small molecular weight and demonstrated allosteric modulating properties of these compound series, show the potential of these scaffolds for future drug development.

References

Finan B, Yang B, Ottaway N, Smiley D, Ma T, Clemmensen C . A rationally designed monomeric peptide triagonist corrects obesity and diabetes in rodents. Nat Med. 2014; 21(1):27-36. DOI: 10.1038/nm.3761. View

Bozorov K, Ma H, Zhao J, Zhao H, Chen H, Bobakulov K . Discovery of diethyl 2,5-diaminothiophene-3,4-dicarboxylate derivatives as potent anticancer and antimicrobial agents and screening of anti-diabetic activity: synthesis and in vitro biological evaluation. Part 1. Eur J Med Chem. 2014; 84:739-45. DOI: 10.1016/j.ejmech.2014.07.065. View

de Graaf C, Donnelly D, Wootten D, Lau J, Sexton P, Miller L . Glucagon-Like Peptide-1 and Its Class B G Protein-Coupled Receptors: A Long March to Therapeutic Successes. Pharmacol Rev. 2016; 68(4):954-1013. PMC: 5050443. DOI: 10.1124/pr.115.011395. View

Redij T, McKee J, Do P, Campbell J, Ma J, Li Z . 2-Aminothiophene derivatives as a new class of positive allosteric modulators of glucagon-like peptide 1 receptor. Chem Biol Drug Des. 2022; 99(6):857-867. PMC: 10278577. DOI: 10.1111/cbdd.14039. View

Malik F, Li Z . Non-peptide agonists and positive allosteric modulators of glucagon-like peptide-1 receptors: Alternative approaches for treatment of Type 2 diabetes. Br J Pharmacol. 2021; 179(4):511-525. PMC: 8820177. DOI: 10.1111/bph.15446. View

Lenharo M . Anti-obesity drug also protects against heart disease - what happens next?. Nature. 2023; 620(7974):480. DOI: 10.1038/d41586-023-02528-2. View

Kang S, Kim N, Yu Y . Identification of novel positive allosteric modulators of GLP1R that stimulate its interaction with ligands and G subunits. Biochem Biophys Res Commun. 2021; 583:162-168. DOI: 10.1016/j.bbrc.2021.10.071. View

Nakamae K, Nishimura Y, Takenaga M, Nakade S, Sakamoto N, Ide H . Establishment of expanded and streamlined pipeline of PITCh knock-in - a web-based design tool for MMEJ-mediated gene knock-in, PITCh designer, and the variations of PITCh, PITCh-TG and PITCh-KIKO. Bioengineered. 2017; 8(3):302-308. PMC: 5470537. DOI: 10.1080/21655979.2017.1313645. View

Zhou Q, Guo W, Dai A, Cai X, Vass M, de Graaf C . Discovery of Novel Allosteric Modulators Targeting an Extra-Helical Binding Site of GLP-1R Using Structure- and Ligand-Based Virtual Screening. Biomolecules. 2021; 11(7). PMC: 8301998. DOI: 10.3390/biom11070929. View

10.

Willard F, Bueno A, Sloop K . Small molecule drug discovery at the glucagon-like peptide-1 receptor. Exp Diabetes Res. 2012; 2012:709893. PMC: 3352573. DOI: 10.1155/2012/709893. View

11.

Sakuma T, Nishikawa A, Kume S, Chayama K, Yamamoto T . Multiplex genome engineering in human cells using all-in-one CRISPR/Cas9 vector system. Sci Rep. 2014; 4:5400. PMC: 4066266. DOI: 10.1038/srep05400. View

12.

Wootten D, Miller L, Koole C, Christopoulos A, Sexton P . Allostery and Biased Agonism at Class B G Protein-Coupled Receptors. Chem Rev. 2016; 117(1):111-138. DOI: 10.1021/acs.chemrev.6b00049. View

13.

Lipinski C . Lead- and drug-like compounds: the rule-of-five revolution. Drug Discov Today Technol. 2014; 1(4):337-41. DOI: 10.1016/j.ddtec.2004.11.007. View

14.

Thanna S, Knudson S, Grzegorzewicz A, Kapil S, Goins C, Ronning D . Synthesis and evaluation of new 2-aminothiophenes against Mycobacterium tuberculosis. Org Biomol Chem. 2016; 14(25):6119-6133. PMC: 4918453. DOI: 10.1039/c6ob00821f. View

15.

Veber D, Johnson S, Cheng H, Smith B, Ward K, Kopple K . Molecular properties that influence the oral bioavailability of drug candidates. J Med Chem. 2002; 45(12):2615-23. DOI: 10.1021/jm020017n. View

16.

El K, Douros J, Willard F, Novikoff A, Sargsyan A, Perez-Tilve D . The incretin co-agonist tirzepatide requires GIPR for hormone secretion from human islets. Nat Metab. 2023; 5(6):945-954. PMC: 10290954. DOI: 10.1038/s42255-023-00811-0. View

17.

Wang J, Yang D, Cheng X, Yang L, Wang Z, Dai A . Allosteric Modulators Enhancing GLP-1 Binding to GLP-1R via a Transmembrane Site. ACS Chem Biol. 2021; 16(11):2444-2452. DOI: 10.1021/acschembio.1c00552. View

18.

Pupo A, Duarte D, Lima V, Teixeira L, Parreiras-E-Silva L, Costa-Neto C . Recent updates on GPCR biased agonism. Pharmacol Res. 2016; 112:49-57. DOI: 10.1016/j.phrs.2016.01.031. View

19.

Pandy-Szekeres G, Munk C, Tsonkov T, Mordalski S, Harpsoe K, Hauser A . GPCRdb in 2018: adding GPCR structure models and ligands. Nucleic Acids Res. 2017; 46(D1):D440-D446. PMC: 5753179. DOI: 10.1093/nar/gkx1109. View

20.

Repasky M, Murphy R, Banks J, Greenwood J, Tubert-Brohman I, Bhat S . Docking performance of the glide program as evaluated on the Astex and DUD datasets: a complete set of glide SP results and selected results for a new scoring function integrating WaterMap and glide. J Comput Aided Mol Des. 2012; 26(6):787-99. DOI: 10.1007/s10822-012-9575-9. View