Orforglipron

• CAT Number: I019672
• CAS Number: 2212020-52-3
• Molecular Formula: C48H48F2N10O5
• Molecular Weight: 882.96
• Purity: ≥95%
• Synonyms: 3-[(1S,2S)-1-[5-[(4S)-2,2-dimethyloxan-4-yl]-2-[(4S)-2-(4-fluoro-3,5-dimethylphenyl)-3-[3-(4-fluoro-1-methylindazol-5-yl)-2-oxoimidazol-1-yl]-4-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carbonyl]indol-1-yl]-2-methylcyclopropyl]-4H-1,2,4-oxadiazol-5-one
• InChI: InChI=1S/C48H48F2N10O5/c1-25-18-32(19-26(2)40(25)49)60-42(58-16-15-57(46(58)63)37-11-10-36-33(41(37)50)24-51-55(36)7)39-28(4)56(14-12-34(39)53-60)43(61)38-21-31-20-29(30-13-17-64-47(5,6)23-30)8-9-35(31)59(38)48(22-27(48)3)44-52-45(62)65-54-44/h8-11,15-16,18-21,24,27-28,30H,12-14,17,22-23H2,1-7H3,(H,52,54,62)/t27-,28-,30-,48-/m0/s1
• InChIKey: USUWIEBBBWHKNI-KHIFEHGGSA-N
• SMILES: CC1CC1(C2=NOC(=O)N2)N3C4=C(C=C(C=C4)C5CCOC(C5)(C)C)C=C3C(=O)N6CCC7=NN(C(=C7C6C)N8C=CN(C8=O)C9=C(C1=C(C=C9)N(N=C1)C)F)C1=CC(=C(C(=C1)C)F)C

Orforglipron (LY3502970) (Compound 67) is an orally active agonist for Glucagon-like peptide-1 receptor (GLP-1R), which exhibits potency in ameliorates the type 2 diabete[1].
Orforglipron is an incretin secreted from L cells of the small intestine when nutrients pass through the digestive tract, and glucose is transmitted via the GLP-1 receptor. Orforglipron exhibits various actions such as dependent gastric emptying delay, and feeding suppression[1].
Orforglipron (0.94-4.8 nM in plasma concentration, i.v., or 0.05-0.1 mg/mL, i.g. for 5 days) suppresses food intake in a dose-dependent manner, promotes insulin secretion and decreases blood glucose in cynomolgus monkey model[1].
Orforglipron (0.05-1.35 mg/kg, i.g.) reaches Cmax 2 hours after administration at all doses, exhibits proportional ratio of increase in plasma drug exposure to dose increase, indicates a dose-dependent absorption in the gastrointestinal tract[1].
Pharmacokinetic Analysis of Orforglipron in cynomolgus monkey [1]

route
Dose (mg/kg)
Tmax (h)
Cmax (ng/mL)
AUC0-24h (ng·h/mL)

i.g.
0.05
2.0
4.78
23.7

i.g.
0.15
2.0
20.7
135

i.g.
0.45
2.0
32.0
208

i.g.
1.35
2.0
148
1040

Reference

[1]. Pyrazolopyridine derivative having glp-1 receptor agonist effect. WO2018056453A1

[2]. Kawai T, Sun B, Yoshino H, et al. Structural basis for GLP-1 receptor activation by LY3502970, an orally active nonpeptide agonist. Proc Natl Acad Sci U S A. 2020;117(47):29959-29967.
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