Neurinostat
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| Drug class | Histone deacetylase inhibitor; Cognitive enhancer |
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| Formula | C19H22N4O3 |
| Molar mass | 354.410 g·mol−1 |
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Neurinostat is a histone deacetylase (HDAC) inhibitor and possible cognitive enhancer.[1][2]
Pharmacology
[edit]| Enzyme | IC50 (nM) |
|---|---|
| HDAC1 | 1.1 |
| HDAC2 | 10.8 |
| HDAC3 | 0.8 |
| HDAC4 | ND |
| HDAC5 | IA |
| HDAC6 | 0.5 |
| HDAC7 | ND |
| HDAC8 | ND |
| HDAC9 | ND |
| HDAC10 | ND |
| HDAC11 | ND |
| Refs: [2] | |
Neurinostat is a histone deacetylase (HDAC) inhibitor and potently inhibits the class I HDAC1, HDAC2, and HDAC3 and the class IIb HDAC6, with IC50 values of 0.5 to 10.8 nM at the preceding HDACs, whereas no activity against the class IIa HDAC5 was observed.[2] Activities at the class I HDAC8 and at the class IIb HDAC4, HDAC7, and HDAC9 were not assessed nor described.[2] The pharmacokinetics of neurinostat in rodents have been studied.[1][2]
Chemistry
[edit]The chemical synthesis of neurinostat has been described.[2] A notable analogue of neurinostat is crebinostat.[1][2]
History
[edit]Neurinostat was first described in the scientific literature by 2016.[1][2] It was derived via structural modification of the earlier HDAC inhibitor crebinostat and differs from this compound only in the replacement of a phenyl ring with a pyridine ring.[1][2] The drug shows enhanced potency as well as modestly improved pharmacokinetics compared to crebinostat.[1][2] In addition, while potency against HDAC1 and HDAC3 was increased, neurinostat showed reduced potency at HDAC2 compared to crebinostat, thus having around 10- to 14-fold selectivity for HDAC1 and HDAC3 over HDAC2.[2]
See also
[edit]References
[edit]- 1 2 3 4 5 6 Ganai SA (2019). "Designing of Selective and Brain-Penetrant HDAC Inhibitors for Effective Therapy Against Neurological Disorders". Histone Deacetylase Inhibitors — Epidrugs for Neurological Disorders. Singapore: Springer Singapore. pp. 65–75. doi:10.1007/978-981-13-8019-8_8. ISBN 978-981-13-8018-1.
Neurinostat, a novel hydroxamate-based HDAC inhibitor, has been designed through logical structural modifications of crebinostat. Previous studies have shown that crebinostat acts as a cognitive enhancer and modulates genes crucial for memory besides promoting synaptogenesis (Fass et al. 2013). Neurinostat has proved to be more potent as compared to crebinostat in inducing histone acetylation (neuronal). Moreover, in mouse brain this inhibitor has been found to have a moderately better pharmacokinetic profile compared to crebinostat (Ghosh et al. 2016).
- 1 2 3 4 5 6 7 8 9 10 11 Ghosh B, Zhao WN, Reis SA, Patnaik D, Fass DM, Tsai LH, et al. (February 2016). "Dissecting structure-activity-relationships of crebinostat: Brain penetrant HDAC inhibitors for neuroepigenetic regulation". Bioorganic & Medicinal Chemistry Letters. 26 (4): 1265–1271. doi:10.1016/j.bmcl.2016.01.022. PMC 4753070. PMID 26804233.