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Incretins include glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), which stimulate insulin secretion post-meals. In type 2 diabetes, GIP's efficacy is reduced, making GLP-1 a viable drug target. GIP originates from preproGIP.
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Repaglinide (Prandin) and Nateglinide (Starlix), known as glinides, are oral insulin secretagogues that stimulate insulin release from pancreatic β cells by closing the ATP-sensitive potassium channels (KATP channel). Repaglinide controls insulin release from pancreatic β cells by managing potassium efflux. It shares two binding sites with sulfonylureas and also has a unique site, indicating overlapping mechanisms of action. With a rapid onset and a 4-7 hour duration, it effectively...
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Dipeptidyl Peptidase 4 Inhibitors01:23

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Dipeptidyl peptidase 4 (DPP-4) is a serine protease widely distributed in the body. It's involved in the inactivation of GLP-1 and GIP hormones, which are crucial for insulin regulation. DPP-4 inhibitors, such as sitagliptin (Januvia), saxagliptin (Onglyza), linagliptin (Tradjenta), alogliptin (Nesina), and vildagliptin (Galvus), help increase the proportion of active GLP-1, enhancing insulin secretion. These inhibitors work by competitively binding to DPP-4. This binding causes a...
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Adrenergic Agonists: Chemistry and Structure-Activity Relationship01:16

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Adrenergic agonists' structure-activity relationship (SAR) determines their selectivity and efficacy. These agonists comprise a phenylethylamine moiety with an aromatic ring and an ethylamine side chain.
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α-glucosidase inhibitors, including acarbose (Precose), miglitol (Glyset), and voglibose (Voglib) (primarily available in Asia), are drugs that control blood sugar levels by delaying the digestion of starch and disaccharides. They achieve this by inhibiting α-glucosidase enzymes in the intestine, which slow the absorption of carbohydrates in the intestine, which in turn leads to a prolonged release of the glucoregulatory hormone GLP-1 from intestinal L-cells.
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Novel Small Molecule GLP-1R Agonists Based on 1H-Benzo[d]imidazole-5-Carboxylic Acid Scaffold.

Elena V Tolkacheva1, Tagir L Salakhov1, Alexandr Yu Saliev1

  • 1Medicinal Biotechnology Department, Sirius University of Science and Technology, Olimpiyskiy Ave. 1, Sirius 354340, Krasnodar Region, Russia.

Molecules (Basel, Switzerland)
|April 14, 2026
PubMed
Summary

Researchers developed new oral glucagon-like peptide-1 receptor agonists (GLP-1RAs) for type 2 diabetes. A potent lead compound, 12r, shows reduced cytotoxicity and good selectivity, offering promise for future diabetes treatments.

Keywords:
1H-benzo[d]imidazole-5-carboxylic acid derivativesGLP-1RAsT2DMcAMP assaysmall molecules“next-in-class” agonists

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Area of Science:

  • Medicinal Chemistry
  • Pharmacology
  • Endocrinology

Background:

  • Glucagon-like peptide-1 (GLP-1) receptor agonists (GLP-1RAs) are crucial for type 2 diabetes treatment.
  • Oral GLP-1RAs are highly sought after, but historically limited to peptide formulations.
  • The development of small molecule agonists like danuglipron opened avenues for oral therapies.

Purpose of the Study:

  • To design and synthesize novel, orally available GLP-1RAs based on a danuglipron scaffold.
  • To evaluate synthesized compounds for cytotoxicity and GLP-1 receptor agonistic activity.
  • To identify lead compounds with improved properties for potential type 2 diabetes treatment.

Main Methods:

  • Synthesis of 35 novel GLP-1RAs based on a 1H-benzo[d]imidazole-5-carboxylic acid scaffold.
  • In vitro evaluation of cytotoxicity (pCC50).
  • Assessment of GLP-1 receptor agonistic activity using a cAMP accumulation assay (pEC50).

Main Results:

  • A potent lead compound, 12r, was identified with a pEC50 of 7.72.
  • Compound 12r demonstrated reduced cytotoxicity (pCC50 < 3.60) compared to related compounds.
  • Excellent selectivity was observed for 12r over glucagon (GCGR) and GIP receptors (GIPR).

Conclusions:

  • The novel danuglipron-like compounds, particularly 12r, show promise as orally available GLP-1RAs.
  • These findings provide valuable structure-activity relationship insights for optimizing future GLP-1RA drug discovery.
  • Further optimization of these compounds could lead to improved therapeutic options for type 2 diabetes mellitus.