For research use only. Not for therapeutic Use.
GNE-7915 tosylate is a potent, selective and brain-penetrant inhibitor of LRRK2 with an IC50 of 9 nM.
Maintaining the methoxy/fluoro arrangement at C-2′/C-5′ and varying aminoalkyl R1 substitution resultes in single-digit nanomolar LRRK2 cellular activities for GNE-7915 and compound 19. Expanded Invitrogen kinase profiling (187 kinases) at 0.1 μM for both GNE-7915 (100-fold over LRRK2 Ki) and 19 (250-fold over LRRK2 Ki) resultes in only TTK showing greater than 50% inhibition. Selectivity profiling using the DiscoverX KinomeScan55 competitive binding assay panel, which includes 392 unique kinases, is also performed for GNE-7915 at 0.1 μM. Binding of >50% probe displacement is detected for 10 kinases and of >65% for only LRRK2, TTK, and ALK, further supporting the excellent LRRK2 selectivity for GNE-7915. Cerep receptor profiling, including expanded brain panels, suggestes that GNE-7915 and 19 only inhibite 5-HT2B with >70% inhibition at 10 μM. GNE-7915 and 19 are confirmed to be moderately potent 5-HT2B antagonists in vitro functional assays[2].
| Catalog Number | I046401 |
| CAS Number | 2070015-00-6 |
| Synonyms | [4-[[4-(ethylamino)-5-(trifluoromethyl)pyrimidin-2-yl]amino]-2-fluoro-5-methoxyphenyl]-morpholin-4-ylmethanone;4-methylbenzenesulfonic acid |
| Molecular Formula | C26H29F4N5O6S |
| Purity | ≥95% |
| InChI | InChI=1S/C19H21F4N5O3.C7H8O3S/c1-3-24-16-12(19(21,22)23)10-25-18(27-16)26-14-9-13(20)11(8-15(14)30-2)17(29)28-4-6-31-7-5-28;1-6-2-4-7(5-3-6)11(8,9)10/h8-10H,3-7H2,1-2H3,(H2,24,25,26,27);2-5H,1H3,(H,8,9,10) |
| InChIKey | VYAOJDYMEMFZKS-UHFFFAOYSA-N |
| SMILES | CCNC1=NC(=NC=C1C(F)(F)F)NC2=C(C=C(C(=C2)F)C(=O)N3CCOCC3)OC.CC1=CC=C(C=C1)S(=O)(=O)O |
| Reference | [1]. Kavanagh ME, et al. The development of CNS-active LRRK2 inhibitors using property-directed optimisation. Bioorg Med Chem Lett.?2013 Jul 1;23(13):3690-6. [2]. Estrada AA, et al. Discovery of highly potent, selective, and brain-penetrable leucine-rich repeat kinase 2 (LRRK2) small molecule inhibitors. J Med Chem. 2012 Nov 26;55(22):9416-33. |
