N -Heterocyclic 3-Pyridyl Carboxamide Inhibitors of DHODH for the Treatment of Acute Myelogenous Leukemia.

Autor: Cisar JS; Janssen Research and Development, 1400 McKean Rd, Spring House, Pennsylvania 19477, United States., Pietsch C; Janssen Research and Development, 1400 McKean Rd, Spring House, Pennsylvania 19477, United States., DeRatt LG; Janssen Research and Development, 1400 McKean Rd, Spring House, Pennsylvania 19477, United States., Jacoby E; Janssen Research and Development, Turnhoutseweg 30, 2340 Beerse, Belgium., Kazmi F; Janssen Research and Development, 1400 McKean Rd, Spring House, Pennsylvania 19477, United States., Keohane C; Janssen Research and Development, 1400 McKean Rd, Spring House, Pennsylvania 19477, United States., Legenski K; Janssen Research and Development, 1400 McKean Rd, Spring House, Pennsylvania 19477, United States., Matico R; Janssen Research and Development, 1400 McKean Rd, Spring House, Pennsylvania 19477, United States., Shaffer P; Janssen Research and Development, 1400 McKean Rd, Spring House, Pennsylvania 19477, United States., Simonnet Y; Janssen Research and Development, 1400 McKean Rd, Spring House, Pennsylvania 19477, United States., Tanner A; Janssen Research and Development, 1400 McKean Rd, Spring House, Pennsylvania 19477, United States., Wang CY; Janssen Research and Development, 1400 McKean Rd, Spring House, Pennsylvania 19477, United States., Wang W; Janssen Research and Development, 1400 McKean Rd, Spring House, Pennsylvania 19477, United States., Attar R; Janssen Research and Development, 1400 McKean Rd, Spring House, Pennsylvania 19477, United States., Edwards JP; Janssen Research and Development, San Diego, California 92121, United States., Kuduk SD; Janssen Research and Development, 1400 McKean Rd, Spring House, Pennsylvania 19477, United States.
Jazyk: angličtina
Zdroj: Journal of medicinal chemistry [J Med Chem] 2022 Aug 25; Vol. 65 (16), pp. 11241-11256. Date of Electronic Publication: 2022 Aug 04.
DOI: 10.1021/acs.jmedchem.2c00788
Abstrakt: Acute myelogenous leukemia (AML), a disease of the blood and bone marrow, is characterized by the inability of myeloblasts to differentiate into mature cell types. Dihydroorotate dehydrogenase (DHODH) is an enzyme well-known in the pyrimidine biosynthesis pathway; however, small molecule DHODH inhibitors were recently shown to induce differentiation in multiple AML subtypes. Using virtual screening and structure-based drug design approaches, a new series of N-heterocyclic 3-pyridyl carboxamide DHODH inhibitors were discovered. Two lead compounds, 19 and 29 , have potent biochemical and cellular DHODH activity, favorable physicochemical properties, and efficacy in a preclinical model of AML.
Databáze: MEDLINE
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