PF-06882961

Biological Activity

PF-06882961 is a potent, orally bioavailable agonist of the glucagon-like peptide-1 receptor (GLP-1R) agonist. PF-06882961 stimulates cAMP accumulation in CHO cells expressing both the human and monkey GLP-1Rs with comparable EC50 values. PF-06882961 shows mild to moderate damage to the heart, moderate to severe effects on the thymus gland (which helps with managing infection), mild to moderate stomach ulcers at the highest dose level given in the rat.

Protocol

Cell Experiment
Cell lines	HEK293 cells
Preparation method	HEK293 cells stably expressing hGLP-1R fused to green fluorescent protein (GFP) (400,000 cells per well) are cultured onto 6 well plates for 24 hours and stimulated with PF-06882961 for 30 minutes. An agonist concentration of 1 μM shown to induce maximal internalization is chosen for these studies. In selected wells, cells are washed three times with PBS containing 0.1 % BSA and incubated at 37 °C for an additional 2 hours to assess reversibility of the endocytosis process. Cells are then fixed with 4% paraformaldehyde for 15 minutes at room temperature followed by three washes with PBS containing 0.1% BSA.
Concentrations	1 μM
Incubation time	30 minutes

Animal Experiment
Animal models	cynomolgus monkeys
Formulation	-
Dosages	1 mg/kg iv; 5 mg/kg, 100 mg/kg PO
Administration	iv, PO

Conversion of different model animals based on BSA (Value based on data from FDA Draft Guidelines)

Species	Mouse	Rat	Rabbit	Guinea pig	Hamster	Dog
Weight (kg)	0.02	0.15	1.8	0.4	0.08	10
Body Surface Area (m2)	0.007	0.025	0.15	0.05	0.02	0.5
Km factor	3	6	12	8	5	20

Animal A (mg/kg) = Animal B (mg/kg) multiplied by	Animal B Km
	Animal A Km

For example, to modify the dose of Compound A used for a mouse (20 mg/kg) to a dose based on the BSA for a rat, multiply 20 mg/kg by the K_m factor for a mouse and then divide by the K_m factor for a rat. This calculation results in a rat equivalent dose for Compound A of 10 mg/kg.

Chemical Information

References

Peptidyl and Non-Peptidyl Oral Glucagon-Like Peptide-1 Receptor Agonists
Hun Jee Choe, et al. Endocrinol Metab (Seoul). 2021 Feb;36(1):22-29. PMID: 33677922.

Design, Synthesis, and Pharmacological Evaluation of Potent Positive Allosteric Modulators of the Glucagon-like Peptide-1 Receptor (GLP-1R)
Maria Mendez, et al. J Med Chem. 2020 Mar 12;63(5):2292-2307. PMID: 31596080.

A small-molecule oral agonist of the human glucagon-like peptide-1 receptor
David A. Griffith, et al. bioRxiv. 2020 Sep.