compound 7 [PMID: 31955578]   Click here for help

GtoPdb Ligand ID: 10649

Compound class: Synthetic organic
Comment: Compound 7 was designed by scientists at Novartis, as a potent and selective brain-penetrant inhibitor of mechanistic target of rapamycin (mTOR) [1]. It is an ATP-competitive inhibitor. It is already established that inhibition of mTOR in the CNS providees clinical efficacy in certain seizure disorders (such as tuberous sclerosis complex; TSC [2]) that are associated with overactivated mTOR signalling [3-4]. The allosteric mTOR inhibitor everolimus is already approved as adjunctive treatment for patients with TSC-associated partial-onset seizures. Compound 7 was optimised to provide a molecule with improved brain permeability compared to everolimus.
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2D Structure
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Physico-chemical Properties
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Hydrogen bond acceptors 8
Hydrogen bond donors 1
Rotatable bonds 3
Topological polar surface area 120.53
Molecular weight 401.16
XLogP 2.22
No. Lipinski's rules broken 0
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Canonical SMILES C[C@@H]1COCCN1c1nc(nc2c1nc(s2)c1n[nH]cc1)N1CCOC[C@@H]1C
Isomeric SMILES C[C@@H]1COCCN1c1nc(nc2c1nc(s2)c1n[nH]cc1)N1CCOC[C@@H]1C
InChI InChI=1S/C18H23N7O2S/c1-11-9-26-7-5-24(11)15-14-17(28-16(20-14)13-3-4-19-23-13)22-18(21-15)25-6-8-27-10-12(25)2/h3-4,11-12H,5-10H2,1-2H3,(H,19,23)/t11-,12+/m1/s1
Bioactivity Comments
As an ATP-competitive inhibitor, compound 7 inhibits mTOR in both mTORC1 and mTORC2 complexes [1], whereas everolimus (an allosteric inhibitor) partially inhibits only mTORC1 complex activity. Favourable brain penetration was observed in mouse and rat following intravenous and oral dosing. Compound 7 inhibits elevated mTOR-induced phosphorylation of S6 ribosomal protein (pS6) in an in vitro mouse model of neuronal Tsc1 knockout, and in rats with mTOR gain-of-function mutations that have been found in focal epilepsy and epileptic genetic syndromes.
Selectivity at enzymes
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Target Sp. Type Action Value Parameter Concentration range (M) Reference
mechanistic target of rapamycin kinase Hs Inhibitor Inhibition 8.3 pIC50 - 1
pIC50 8.3 (IC50 5.6x10-9 M) [1]
Description: IC50 for inhibition of mTOR-induced phosphorylation of S6 protein in a cellular assay.
phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit delta Hs Inhibitor Inhibition 5.8 pIC50 - 1
pIC50 5.8 (IC50 1.7x10-6 M) [1]
phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha Hs Inhibitor Inhibition 5.7 pIC50 - 1
pIC50 5.7 (IC50 2.2x10-6 M) [1]