PKI-179 is a potent and orally active dual PI3K mTOR inhibitor, with IC50s of 8 nM, 24 nM, 74 nM, 77 nM, and 0.42 nM for PI3K-α, PI3K-β, PI3K-γ, PI3K-δ and mTOR, respectively. PKI-179 also exhibits activity over E545K and H1047R, with IC50s of 14 nM and 11 nM, respectively. PKI-179 shows anti-tumor activity in vivo[1][2]. PKI-179 inhibits the cell proliferation, with IC50s of 22 nM and 29 nM for MDA361 and PC3 cells, respectively[1].PKI-179 shows inhibitory activity against a panel of 361 other kinases, hERG and cytochrome P450 (CYP) isoforms at concentrations up to >30 μM, but does have activity for CYP2C8 (IC50=3 μM)[1]. PKI-179 (5-50 mg kg; p.o. once daily for 40 days) inhibits the tumor growth and is well tolerated in nude mice bearing MDA-361 human breast cancer tumors[1].PKI-179 (50 mg kg; p.o.) results in good inhibition of PI3K signaling in nude mice bearing MDA361 tumor xenografts[1].PKI-179 exhibits good oral bioavailability (98% in nude mouse, 46% in rat, 38% in monkey, and 61% in dog) and a high half-life (>60 min) [1]. [1]. Venkatesan AM, et, al. PKI-179: an orally efficacious dual phosphatidylinositol-3-kinase (PI3K) mammalian target of rapamycin (mTOR) inhibitor. Bioorg Med Chem Lett. 2010 Oct 1;20(19):5869-73.[2]. Rehan M. A structural insight into the inhibitory mechanism of an orally active PI3K mTOR dual inhibitor, PKI-179 using computational approaches. J Mol Graph Model. 2015 Nov;62:226-234.
Celecoxib carboxylic acid is an inactive metabolite of the COX-2 inhibitor celecoxib .1,2It is formed from celecoxib primarily by the cytochrome P450 (CYP) isoform CYP2C9. 1.Liu, H., Huang, X., Shen, J., et al.Inhibitory mode of 1,5-diarylpyrazole derivatives against cyclooxygenase-2 and cyclooxygenase-1: Molecular docking and 3D QSAR analysesJ. Med. Chem.45(22)4816-4827(2002) 2.Kim, S.-H., Kim, D.-H., Byeon, J.-Y., et al.Effects of CYP2C9 genetic polymorphisms on the pharmacokinetics of celecoxib and its carboxylic acid metaboliteArch. Pharm. Res.40(3)382-390(2017)
Desethoxy quetiapine, an active metabolite of the atypical antipsychotic quetiapine, primarily forms through the action of the cytochrome P450 (CYP) isoform CYP3A5. This compound binds to dopamine D2 receptors with an IC50 value of 1,330 nM. In vivo, desethoxy quetiapine at dosages of 20 and 40 mg kg mitigates dopamine receptor agonist apomorphine-induced climbing behavior and ameliorates swimming deficits in mice, showcasing its potential modulatory effects on dopamine-mediated behaviors.