Novel GPRC6A Agonists to Treat T2 Diabetes and Metabolic Syndrome
A critical barrier in preventing and treating T2D is the lack of a druggable target that simultaneously treats the multiple abnormalities associated with T2D that include impaired insulin secretion and chronic β-cell decompensation, owing to impaired glucose-sensing and insufficient increases in β-cell mass, and peripheral insulin resistance, due to alterations in muscle and liver metabolism. None of the currently prescribed drugs simultaneously target the multiple abnormalities, and they consequently have limited effectiveness, requiring multiple drug combinations.
The Technology Solution:
GPRC6A is a nutrient sensing receptor that regulates energy metabolism. The inventors found that activating GPRC6A yields a strong therapeutic effect for diabetes by directly stimulating insulin secretion from pancreatic β-cells and maintaining β-cell mass. That directly impacts peripheral tissue metabolic functions to increase insulin sensitivity in liver, muscle and adipose tissues. It drives hepatocytes to increase glucose and fatty acid uptake and stimulates the release of FGF-21 to enhance glucose uptake.
For the activation of GPRC6A we designed and synthesized novel GPRC6A agonists, starting from virtual high throughput screening hits. Functional analysis of these compounds in vitro confirmed their effect on GPRC6A activation.
Going from hit to early discovery lead, SAR analysis identified the most active compounds that increased the insulin stimulation index ex-vivo in wild-type isolated pancreatic islets to a level similar to Osteocalcin, a benchmark ligand of GPRC6A (Fig 1 A).
In-vivo studies with the current lead reduced the blood glucose levels by 43.6% after 60 min at a dose of 10 mg/kg in wild-type mice (Fig. 1 B). Metformin, the first-line medication for T2D, resulted in similar reductions in blood glucose, but only at a much higher dose of 300 mg/kg, not 10 mg/kg as with our lead (Fig 1 D).
The project currently aims to de-risk leads with ADME/toxicity screens and find the compound with the best PK properties.
MOLECULAR METABOLISM 6 (2017) 185-193
Provisional Patent filed August 2017
- Lowers blood glucose levels in vivo similar to first line medication Metformin at 30 x lower dose.
- Increases insulin stimulation in pancreatic islets similar to benchmark ligand Osteocalcin.
- Small molecule agonists with robust and reliable synthesis.