Download MendeleyIdentification of isoquinolinone DHODH inhibitor isosteres.
DeRatt, L.G., Zhang, Z., Pietsch, E.C., Cisar, J., Wang, A., Wang, C.Y., Tanner, A., Shaffer, P., Jacoby, E., Kazmi, F., Shukla, N., Philippar, U., Attar, R.M., Edwards, J.P., Kuduk, S.D.(2024) Bioorg Med Chem Lett 113: 129965-129965
- PubMed: 39284456
- DOI: https://doi.org/10.1016/j.bmcl.2024.129965
- Primary Citation of Related Structures:
9DHG, 9DHH, 9DHI, 9DHJ - PubMed Abstract:
DHODH inhibition represents an attractive approach to overcome differentiation blockade for the treatment of AML. In a previous communication, we described our efforts leading to the discovery of compound 3 (JNJ-74856665), an orally bioavailable, potent, and selective DHODH inhibitor for clinical development. Guided by the co-crystal structures bound to human DHODH, other fused six-membered constructs were explored as isosteric replacements of the isoquinolinone central core. The correct positioning of the nitrogen in these core systems proved to be essential in modulating potency. Herein is described the synthesis of these complexly functionalized cores and their profiling, leading to DHODH inhibitors that possess favorable properties suitable for further development.
Organizational Affiliation:
Janssen Research and Development, Spring House, PA 19477, USA. Electronic address: [email protected].
