TAK-063

• CAT Number: I000951
• CAS Number: 1238697-26-1
• Molecular Formula: C₂₃H₁₇FN₆O₂
• Molecular Weight: 428.42
• Purity: ≥95%
• Target: PDE10A
• Solubility: 10 mM in DMSO
• Storage: -20°C
• IC50: 0.3 nM
• InChI: InChI=1S/C23H17FN6O2/c1-32-21-15-29(19-9-8-17(14-18(19)24)28-13-5-11-25-28)27-22(23(21)31)20-10-12-26-30(20)16-6-3-2-4-7-16/h2-15H,1H3
• InChIKey: KVHRYLNQDWXAGI-UHFFFAOYSA-N
• SMILES: COC1=CN(N=C(C1=O)C2=CC=NN2C3=CC=CC=C3)C4=C(C=C(C=C4)N5C=CC=N5)F

TAK-063 is a highly potent, selective and orally active PDE10A inhibitor with IC50 of 0.30 nM; >15000-fold selectivity over other PDEs. TAK-063 has potent inhibitory activity (IC50 = 0.30 nM), excellent selectivity (>15000-fold selectivity over other PDEs), and favorable pharmacokinetics, including high brain penetration, in mice. Oral administration of TAK-063 to mice elevated striatal 3/’,5/’-cyclic adenosine monophosphate (cAMP) and 3/’,5/’-cyclic guanosine monophosphate (cGMP) levels at 0.3 mg/kg and showed potent suppression of phencyclidine (PCP)-induced hyperlocomotion at a minimum effective dose (MED) of 0.3 mg/kg [1]. TAK-063 at 0.3 and 1 mg/kg, p.o., increased cAMP and cGMP levels in the rodent striatum and upregulated phosphorylation levels of key substrates of cAMP-dependent and cGMP-dependent protein kinases. TAK-063 at 0.3 and 1 mg/kg, p.o., strongly suppressed MK-801-induced hyperlocomotion that is often used as a predictive model for antipsychotic-like activity in rodents. TAK-063 did not affect plasma prolactin or glucose levels at doses up to 3 mg/kg, p.o. TAK-063 at 3 mg/kg, p.o., elicited a weak cataleptic response compared with haloperidol and olanzapine [2].

Reference

1:A strategy to improve the success rate of CNS drug development: TAK-063, a novel PDE10A inhibitor, as a case study. Kimura H.Nihon Yakurigaku Zasshi. 2017;149(4):160-166. doi: 10.1254/fpj.149.160. No abstract available. PMID: 28381659
2:TAK-063, a Novel Phosphodiesterase 10A Inhibitor, Protects from Striatal Neurodegeneration and Ameliorates Behavioral Deficits in the R6/2 Mouse Model of Huntington/’s Disease. Harada A, Suzuki K, Kimura H.J Pharmacol Exp Ther. 2017 Jan;360(1):75-83. Epub 2016 Nov 3. PMID: 27811172
3:TAK-063, a phosphodiesterase 10A inhibitor, modulates neuronal activity in various brain regions in phMRI and EEG studies with and without ketamine challenge. Tomimatsu Y, Cash D, Suzuki M, Suzuki K, Bernanos M, Simmons C, Williams SC, Kimura H.Neuroscience. 2016 Dec 17;339:180-190. doi: 10.1016/j.neuroscience.2016.10.006. Epub 2016 Oct 8. PMID: 27725212
4:A phase 1 study of the safety, tolerability, pharmacokinetics, and pharmacodynamics of TAK-063, a selective PDE10A inhibitor. Tsai M, Chrones L, Xie J, Gevorkyan H, Macek TA.Psychopharmacology (Berl). 2016 Oct;233(21-22):3787-3795. Epub 2016 Aug 30. PMID: 27572830 Free PMC Article
5:A human [(11)C]T-773 PET study of PDE10A binding after oral administration of TAK-063, a PDE10A inhibitor. Takano A, Stenkrona P, Stepanov V, Amini N, Martinsson S, Tsai M, Goldsmith P, Xie J, Wu J, Uz T, Halldin C, Macek TA.Neuroimage. 2016 Nov 1;141:10-7. doi: 10.1016/j.neuroimage.2016.06.047. Epub 2016 Jul 15. PMID: 27423256
6:Brain PET measurement of PDE10A occupancy by TAK-063, a new PDE10A inhibitor, using [11 C]T-773 in nonhuman primates. Takano A, Stepanov V, Nakao R, Amini N, Gulyás B, Kimura H, Halldin C.Synapse. 2016 Jun;70(6):253-63. doi: 10.1002/syn.21896. Epub 2016 Mar 4. PMID: 26878349
7:TAK-063, a PDE10A Inhibitor with Balanced Activation of Direct and Indirect Pathways, Provides Potent Antipsychotic-Like Effects in Multiple Paradigms. Suzuki K, Harada A, Suzuki H, Miyamoto M, Kimura H.Neuropsychopharmacology. 2016 Aug;41(9):2252-62. doi: 10.1038/npp.2016.20. Epub 2016 Feb 5. PMID: 26849714
8:The Phosphodiesterase 10A Selective Inhibitor TAK-063 Improves Cognitive Functions Associated with Schizophrenia in Rodent Models. Shiraishi E, Suzuki K, Harada A, Suzuki N, Kimura H.J Pharmacol Exp Ther. 2016 Mar;356(3):587-95. doi: 10.1124/jpet.115.230482. Epub 2015 Dec 16. PMID: 26675680 Free Article
9:Characterization of binding and inhibitory properties of TAK-063, a novel phosphodiesterase 10A inhibitor. Harada A, Suzuki K, Kamiguchi N, Miyamoto M, Tohyama K, Nakashima K, Taniguchi T, Kimura H.PLoS One. 2015 Mar 27;10(3):e0122197. doi: 10.1371/journal.pone.0122197. eCollection 2015. PMID: 25815469 Free PMC Article
10:In vivo pharmacological characterization of TAK-063, a potent and selective phosphodiesterase 10A inhibitor with antipsychotic-like activity in rodents. Suzuki K, Harada A, Shiraishi E, Kimura H.J Pharmacol Exp Ther. 2015 Mar;352(3):471-9. doi: 10.1124/jpet.114.218552. Epub 2014 Dec 18. PMID: 25525190 Free Article