Fragment-based discovery of 6-substituted isoquinolin-1-amine based ROCK-I inhibitors.

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Ray P, Wright J, Adam J, Bennett J, Boucharens S, Black D, Cook A, Brown AR, Epemolu O, Fletcher D, Haunso A, Huggett M, Jones P, Laats S, Lyons A, Mestres J, de Man J, Morphy R, Rankovic Z, Sherborne B, Sherry L, van Straten N, Westwood P, Zaman GZ

Fragment-based discovery of 6-substituted isoquinolin-1-amine based ROCK-I inhibitors.

Bioorg Med Chem Lett. 2011 Jan 1;21(1):97-101. doi: 10.1016/j.bmcl.2010.11.060. Epub 2010 Nov 19.

PubMed ID
21145740 [ View in PubMed
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Abstract

Fragment-based NMR screening of a small literature focused library led to identification of a historical thrombin/FactorXa building block, 17A, that was found to be a ROCK-I inhibitor. In the absence of an X-ray structure, fragment growth afforded 6-substituted isoquinolin-1-amine derivatives which were profiled in the primary ROCK-I IMAP assay. Compounds 23A and 23E were selected as fragment optimized hits for further profiling. Compound 23A has similar ROCK-1 affinity, potency and cell based efficacy to the first generation ROCK inhibitors, however, it has a superior PK profile in C57 mouse. Compound 23E demonstrates the feasibility of improving ROCK-1 affinity, potency and cell based efficacy for the series, however, it has a poor PK profile relative to 23A.

DrugBank Data that Cites this Article

Binding Properties
DrugTargetPropertyMeasurementpHTemperature (°C)
FasudilRho-associated protein kinase 1IC 50 (nM)3162.28N/AN/ADetails
FasudilRho-associated protein kinase 1Ki (nM)100N/AN/ADetails
FasudilRho-associated protein kinase 2IC 50 (nM)1348.96N/AN/ADetails
HydroxyfasudilRho-associated protein kinase 1IC 50 (nM)758.58N/AN/ADetails
HydroxyfasudilRho-associated protein kinase 1Ki (nM)31.62N/AN/ADetails
Y-27632Rho-associated protein kinase 1IC 50 (nM)870.96N/AN/ADetails
Y-27632Rho-associated protein kinase 1Ki (nM)25.12N/AN/ADetails
Y-27632Rho-associated protein kinase 2IC 50 (nM)245.47N/AN/ADetails