AMG319

• CAT Number: I002045
• CAS Number: 1608125-21-8
• Molecular Formula: C21H16FN7
• Molecular Weight: 385.40
• Purity: ≥95%
• Synonyms: N-[(1S)-1-(7-fluoro-2-pyridin-2-ylquinolin-3-yl)ethyl]-7H-purin-6-amine
• InChI: InChI=1S/C21H16FN7/c1-12(28-21-19-20(25-10-24-19)26-11-27-21)15-8-13-5-6-14(22)9-17(13)29-18(15)16-4-2-3-7-23-16/h2-12H,1H3,(H2,24,25,26,27,28)/t12-/m0/s1
• InChIKey: KWRYMZHCQIOOEB-LBPRGKRZSA-N
• SMILES: CC(C1=C(N=C2C=C(C=CC2=C1)F)C3=CC=CC=N3)NC4=NC=NC5=C4NC=N5

AMG319 is a potent and selective PI3Kδ kinase inhibitor with IC50 of 18 nM.
AMG319 inhibits PI3Kδ, PI3Kγ, PI3Kβ and PI3Kα with IC50s of 18 nM, 850 nM, 2.7 μM and 33 μM, respectively. AMG319, a compound with an IC50 of 16 nM in a human whole blood assay (HWB), excellent selectivity over a large panel of protein kinases, and a high level of in vivo efficacy as measured by two rodent disease models of inflammation. AMG319 has minimal CYP3A4/2D6 inhibition and does not inhibit CYPs (1A2, 2C8, 2C9, 2C19, 2E1, all >20 μM). There is no time dependent inhibition (TDI) against CYPs 3A4, 2D6, 1A2, and 2C9 nor CYP induction (3A4, 2D6, 1A2, 2B6) as measured in hepatocytes. AMG319 is clean in a hERG binding assay (>25 μM), and an Ames micronucleus test proved negative. AMG319 has minimal effects in a BSEP assay up to >200 μM[1].
The study is performed to determine the correlation between biochemical coverage (i.e., pAKT) with functional activity in vivo. AMG319 achieves this coverage at the 3 mg/kg level, which also coveres the human whole blood assay (HWB) (CD-69) IC90 at trough for a full 24 h period. The lower doses 0.1, 0.3, and 1 mg/kg cover trough concentrations between the HWB IC50 and IC90 and evince partial efficacy. Similarly, the plasma concentration of AMG319 covers the IC90 at the 1 mg/kg dose of the mouse anti-IgM pAKT in vitro assay[1].

Reference

[1]. Cushing TD, et al. Discovery and in vivo evaluation of (S)-N-(1-(7-fluoro-2-(pyridin-2-yl)quinolin-3-yl)ethyl)-9H-purin-6-amine (AMG319) and related PI3Kδ inhibitors for inflammation and autoimmune disease. J Med Chem. 2015 Jan 8;58(1):480-511.
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