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
1. Bonazzi S, Goold CP, Gray A, Thomsen NM, Nunez J, Karki RG, Gorde A, Biag JD, Malik HA, Sun Y et al.. (2020)
Discovery of a Brain-Penetrant ATP-Competitive Inhibitor of the Mechanistic Target of Rapamycin (mTOR) for CNS Disorders.
J Med Chem, 63 (3): 1068-1083. [PMID:31955578]
2. Iffland 2nd PH, Crino PB. (2019)
The role of somatic mutational events in the pathogenesis of epilepsy.
Curr Opin Neurol, 32 (2): 191-197. [PMID:30762606]
3. Koh HY, Lee JH. (2018)
Brain Somatic Mutations in Epileptic Disorders.
Mol Cells, 41 (10): 881-888. [PMID:30352490]
4. Lim JS, Kim WI, Kang HC, Kim SH, Park AH, Park EK, Cho YW, Kim S, Kim HM, Kim JA et al.. (2015)
Brain somatic mutations in MTOR cause focal cortical dysplasia type II leading to intractable epilepsy.
Nat Med, 21 (4): 395-400. [PMID:25799227]