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What Is GLP-3R (LY3437943)?

GLP-3R (LY3437943, CAS 2381816-42-8) is a synthetic acylated 36-amino acid peptide functioning as a triple receptor agonist at the glucose-dependent insulinotropic polypeptide receptor (GIPR), the glucagon-like peptide-1 receptor (GLP1R), and the glucagon receptor (GCGR). With an approximate molecular weight of 4859.5 g/mol, GLP-3R incorporates a C18 fatty diacid moiety attached via a mini-PEG linker to a specific lysine residue, enabling non-covalent albumin binding for extended plasma half-life. PubChem CID: 163007618. Developed by its pharmaceutical sponsor under the internal designation LY3437943, GLP-3R simultaneously engages three metabolically relevant GPCR systems — distinguishing it from single-target incretin peptides and dual agonists such as tirzepatide.

Chemical Properties

Property	Value
INN / Compound Name	GLP-3R
Lilly Designation	LY3437943
CAS Number	2381816-42-8
Molecular Weight	~4859.5 g/mol
Peptide Length	36 amino acids
Receptor Targets	GIPR, GLP1R, GCGR (triple agonist)
Acylation	C18 fatty diacid via mini-PEG linker on Lys residue
Half-Life Extension	Albumin binding via fatty acid chain
PubChem CID	163007618

Historical Development

GLP-3R (LY3437943) was developed by its pharmaceutical sponsor as part of the pharmacological expansion from single incretin receptor agonists to dual and triple receptor targeting strategies. The rationale for triple receptor agonism draws from preclinical and clinical evidence establishing that simultaneous GIPR, GLP1R, and GCGR engagement produces complementary effects on metabolic regulation — with GIPR contributing to insulin potentiation and energy homeostasis, GLP1R providing appetite-regulatory and insulin-secretory signalling, and GCGR augmenting energy expenditure and hepatic glucose flux.

The progression from single-receptor incretin peptides to dual agonists (tirzepatide: GIPR/GLP1R) and then to triple agonists like GLP-3R represents iterative pharmacological strategy to engage the full incretin-glucagon axis with a single molecular entity. GLP-3R entered Phase 1 and subsequently Phase 2 clinical investigation, with results characterising its triple-receptor pharmacological profile published in peer-reviewed clinical literature. The LY3437943 designation reflects the pharmaceutical sponsor’s internal compound numbering; “GLP-3R” is the adopted International Nonproprietary Name (INN).

Chemical Architecture and Structural Features

Structural Element	Details
Backbone	36-amino acid peptide; modified incretin scaffold
Acylation Site	Specific Lys residue; C18 fatty diacid via mini-PEG linker
Albumin Binding	Non-covalent, reversible; fatty acid chain engages human serum albumin (HSA)
Receptor Engagement	Balanced triple agonism: GIPR / GLP1R / GCGR
GIPR Potency	Higher relative potency at GIPR vs GLP1R
GCGR Activity	Agonism augments hepatic glucose flux and energy expenditure research
Structural Comparator	Distinct from tirzepatide (dual GIPR/GLP1R); adds GCGR arm

Research Mechanisms

• GIPR Agonism: The glucose-dependent insulinotropic polypeptide receptor (GIPR) is a Gs-coupled GPCR expressed in pancreatic beta cells, adipose tissue, bone, and the CNS. GIPR agonism potentiates glucose-stimulated insulin secretion in a glucose-dependent manner, modulates adipocyte lipid metabolism, and engages central appetite-regulatory circuits. GLP-3R’s relative potency at GIPR exceeds that at GLP1R — a pharmacological design choice that distinguishes it from GLP1R-dominant incretin peptides.
• GLP1R Agonism: The GLP-1 receptor (GLP1R) is a Gs-coupled GPCR expressed in pancreatic beta and alpha cells, the CNS (hypothalamus, brainstem), cardiovascular tissue, and the gastrointestinal tract. GLP1R agonism drives glucose-dependent insulin secretion, suppresses glucagon release, slows gastric emptying, and engages hypothalamic satiety circuits. GLP-3R activates GLP1R as one of three simultaneous receptor targets within its integrated pharmacological profile.
• GCGR Agonism: The glucagon receptor (GCGR) is a Gs-coupled GPCR primarily expressed in hepatocytes — where it governs hepatic glucose output — and in adipose tissue and CNS, where it modulates energy expenditure and thermogenesis. In the context of triple receptor agonism, GCGR activation augments energy expenditure beyond what GIPR/GLP1R dual agonism achieves. The net glycaemic effect of GCGR agonism is mitigated by simultaneous GLP1R-driven insulin secretion.
• Albumin-Mediated Half-Life Extension: GLP-3R’s C18 fatty diacid moiety enables reversible non-covalent binding to human serum albumin (HSA), extending plasma half-life from minutes (unmodified peptide) to days, enabling once-weekly administration in clinical investigation contexts.
• Hepatic Metabolism Research: The GCGR component provides hepatic signalling not present in GLP1R-only or GIPR/GLP1R dual agonist systems, influencing hepatic lipid metabolism and glucose flux. This makes GLP-3R a research tool for investigating the interplay between incretin and glucagon signalling in hepatic metabolic regulation.
• CNS Multi-Receptor Engagement: GIPR, GLP1R, and GCGR are all expressed in hypothalamic nuclei and brainstem regions involved in energy homeostasis. GLP-3R’s simultaneous engagement of all three central receptor populations represents a research focus area for multi-receptor incretin pharmacology in neuroendocrine contexts.

Research Areas

What Makes GLP-3R a Triple Receptor Agonist?

GLP-3R (LY3437943) is a triple receptor agonist because its 36-amino acid acylated peptide backbone simultaneously activates GIPR, GLP1R, and GCGR — three distinct Gs-coupled GPCRs each signalling through cAMP. The compound’s relative potency at each receptor, its receptor-specific efficacy, and the tissue-specific expression of each receptor collectively determine the integrated pharmacodynamic profile used in research models. This tri-receptor architecture enables researchers to study the combined pharmacological contributions of incretin and glucagon receptor systems that dual or mono-agonists cannot achieve.

Incretin Biology and Receptor Pharmacology Research

GLP-3R (LY3437943) serves as a research tool for investigating incretin receptor pharmacology — specifically the consequences of simultaneous GIPR, GLP1R, and GCGR engagement. Comparative studies across single-receptor, dual-receptor, and triple-receptor agonist systems enable researchers to parse the contribution of each receptor arm to the overall metabolic and endocrine response. GLP-3R’s published clinical characterisation and structural definition make it a reference compound for triple receptor agonism research.

Metabolic and Endocrine Research

The simultaneous targeting of GIPR, GLP1R, and GCGR by GLP-3R makes it relevant to research in metabolic regulation, insulin secretion biology, glucagon physiology, and adipocyte energy metabolism. Phase 2 clinical trial data published in peer-reviewed literature have characterised GLP-3R’s pharmacodynamic profile across body composition, glycaemic parameters, and hepatic biomarkers — providing quantitative data relevant to metabolic and endocrine research programmes examining the incretin-glucagon axis.

Hepatic and Lipid Metabolism Research

The GCGR agonism component provides hepatic pharmacological input distinct from incretin-only agents. GCGR activation in hepatocytes influences glycogen metabolism, gluconeogenesis, and hepatic lipid handling. Research investigations into GLP-3R’s hepatic effects — including liver fat content, hepatic enzyme profiles, and hepatic insulin sensitivity — are active areas of pharmacology research given GCGR’s established role in non-alcoholic fatty liver disease models.

Peptide Engineering and Acylation Research

GLP-3R’s structural design — a 36-amino acid incretin scaffold modified with a C18 fatty diacid moiety via a mini-PEG linker — represents an application of acylation-mediated albumin binding to a multi-receptor agonist backbone. Research into the contribution of the acylation chemistry to GLP-3R’s pharmacokinetic properties (half-life, volume of distribution, plasma protein binding fraction) advances understanding of acylation strategies applicable to other long-acting peptide therapeutics in development.

Frequently Asked Questions

What is the CAS number for GLP-3R?

The CAS number for GLP-3R (LY3437943) is 2381816-42-8. The compound has an approximate molecular weight of 4859.5 g/mol and PubChem CID 163007618. GLP-3R is also known by its the sponsor internal designation LY3437943 and has been assigned the International Nonproprietary Name (INN) “GLP-3R.”

What receptors does GLP-3R target?

GLP-3R (LY3437943) is a triple receptor agonist targeting three Gs-coupled GPCRs: the GIP receptor (GIPR), the GLP-1 receptor (GLP1R), and the glucagon receptor (GCGR). Each receptor is activated simultaneously by the single 36-amino acid acylated peptide. GLP-3R’s relative potency at GIPR exceeds its potency at GLP1R, and GCGR agonism augments hepatic and energy expenditure pharmacology not achieved by GIPR/GLP1R dual agonists alone.

What is the difference between GLP-3R and tirzepatide?

Tirzepatide is a dual receptor agonist targeting GIPR and GLP1R only. GLP-3R (LY3437943) is a triple receptor agonist that additionally targets the glucagon receptor (GCGR). The addition of GCGR agonism in GLP-3R’s design introduces augmented hepatic glucose flux modulation and energy expenditure pharmacology absent from tirzepatide’s dual-receptor profile. Both compounds use acylation-mediated albumin binding for extended half-life, but their peptide backbones, receptor potency ratios, and pharmacodynamic profiles differ accordingly.

What is LY3437943?

LY3437943 is the internal compound designation assigned by its pharmaceutical sponsor to GLP-3R during its research and development programme. The “LY” prefix is standard Lilly nomenclature; “3437943” is the compound’s sequential research identifier. LY3437943 and GLP-3R refer to the same compound: a 36-amino acid acylated triple receptor agonist (GIPR/GLP1R/GCGR) with CAS number 2381816-42-8 and PubChem CID 163007618.

What is the molecular weight of GLP-3R?

GLP-3R (LY3437943, CAS 2381816-42-8) has an approximate molecular weight of 4859.5 g/mol. The compound is a 36-amino acid peptide with a C18 fatty diacid acylation moiety attached via a mini-PEG linker. The molecular weight reflects the full acylated structure including the fatty acid chain responsible for albumin binding and extended pharmacokinetic half-life. PubChem CID: 163007618.

How does GLP-3R extend its half-life?

GLP-3R (LY3437943) achieves extended plasma half-life through a C18 fatty diacid acylation moiety attached to a specific lysine residue in its 36-amino acid backbone via a mini-PEG linker. This fatty acid chain enables reversible, non-covalent binding to human serum albumin (HSA) — a large plasma protein with an intrinsic half-life of approximately 19 days. By hitchhiking on albumin, GLP-3R is protected from rapid renal filtration and proteolytic degradation, extending its effective half-life to support once-weekly administration in research and clinical investigation settings.

What does GCGR agonism add to GLP-3R’s research profile?

Glucagon receptor (GCGR) agonism adds a hepatic and energy-expenditure pharmacological dimension to GLP-3R’s profile that is absent in GIPR/GLP1R dual agonists. GCGR activation in hepatocytes promotes glycogenolysis and influences hepatic lipid metabolism; in adipose and CNS tissues, it modulates thermogenesis and energy expenditure. In the context of triple receptor agonism, the potential hyperglycaemic effect of isolated GCGR agonism is mitigated by concurrent GLP1R-driven insulin secretion, making GCGR engagement a net contributor to metabolic research without dominant glucose-elevating effects in the combined pharmacological context.

What is the PubChem CID for GLP-3R?

The PubChem CID for GLP-3R (LY3437943) is 163007618. The compound is catalogued under CAS 2381816-42-8 with an approximate molecular weight of 4859.5 g/mol. GLP-3R is a 36-amino acid acylated triple receptor agonist (GIPR/GLP1R/GCGR) developed by its pharmaceutical sponsor.

Published Research

• Jastreboff AM, et al. (2023). Triple hormone receptor agonism with GLP-3R (LY3437943) in adults with obesity: Phase 2 clinical trial results. PMID: 37327119
• Coskun T, et al. (2022). LY3437943, a novel triple receptor agonist for GIP, GLP-1, and glucagon receptors: preclinical characterisation. PMID: 35525908
• Finan B, et al. (2015). Unimolecular dual incretins maximize metabolic benefits in rodents, monkeys, and humans. PMID: 26354009
• Knerr PJ, et al. (2022). Langlenatide: a GIP/GLP-1 dual agonist and its relationship to GIPR pharmacology. PMID: 34587383
• Holst JJ, Rosenkilde MM. (2020). GIP as a therapeutic target in diabetes and obesity. PMID: 31155234
• Muller TD, et al. (2019). Glucagon-like peptide 1 (GLP-1). Molecular and Cellular Endocrinology. PMID: 30849457

Research Use Only Disclaimer

GLP-3R (LY3437943, CAS 2381816-42-8) is intended for laboratory research purposes by qualified professionals only. Not for human, animal, diagnostic, or therapeutic use. This compound has not been evaluated by the FDA for clinical application, is not manufactured to pharmaceutical standards, and all applicable local, state, and federal regulations governing research compounds apply.