Discovery of 2-(6-{[(6-fluoroquinolin-2-yl)methyl]amino}bicyclo[3.1.0]hex-3-yl)-N-hydroxypyrim idine-5-carboxamide (CHR-3996), a class I selective orally active histone deacetylase inhibitor.

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Moffat D, Patel S, Day F, Belfield A, Donald A, Rowlands M, Wibawa J, Brotherton D, Stimson L, Clark V, Owen J, Bawden L, Box G, Bone E, Mortenson P, Hardcastle A, van Meurs S, Eccles S, Raynaud F, Aherne W

Discovery of 2-(6-{[(6-fluoroquinolin-2-yl)methyl]amino}bicyclo[3.1.0]hex-3-yl)-N-hydroxypyrim idine-5-carboxamide (CHR-3996), a class I selective orally active histone deacetylase inhibitor.

J Med Chem. 2010 Dec 23;53(24):8663-78. doi: 10.1021/jm101177s. Epub 2010 Nov 16.

PubMed ID
21080647 [ View in PubMed
]
Abstract

A novel series of HDAC inhibitors demonstrating class I subtype selectivity and good oral bioavailability is described. The compounds are potent enzyme inhibitors (IC(5)(0) values less than 100 nM), and improved activity in cell proliferation assays was achieved by modulation of polar surface area (PSA) through the introduction of novel linking groups. Employing oral pharmacokinetic studies in mice, comparing drug levels in spleen to plasma, we selected compounds that were tested for efficacy in human tumor xenograft studies based on their potential to distribute into tumor. One compound, 21r (CHR-3996), showed good oral activity in these models, including dose-related activity in a LoVo xenograft. In addition 21r showed good activity in combination with other anticancer agents in in vitro studies. On the basis of these results, 21r was nominated for clinical development.

DrugBank Data that Cites this Article

Binding Properties
DrugTargetPropertyMeasurementpHTemperature (°C)
VorinostatHistone deacetylase 1IC 50 (nM)30N/AN/ADetails
VorinostatHistone deacetylase 2IC 50 (nM)24N/AN/ADetails
VorinostatHistone deacetylase 3IC 50 (nM)150N/AN/ADetails
VorinostatHistone deacetylase 6IC 50 (nM)30N/AN/ADetails