1. Optimization of Tetrahydroindazoles as Inhibitors of Human Dihydroorotate Dehydrogenase and Evaluation of Their Activity and In Vitro Metabolic Stability.
- Author
-
Popova G, Ladds MJGW, Johansson L, Saleh A, Larsson J, Sandberg L, Sahlberg SH, Qian W, Gullberg H, Garg N, Gustavsson AL, Haraldsson M, Lane D, Yngve U, and Lain S
- Subjects
- Animals, Cell Survival drug effects, Cell Survival physiology, Dihydroorotate Dehydrogenase, Dose-Response Relationship, Drug, Drug Evaluation, Preclinical methods, Enzyme Inhibitors pharmacology, Female, Humans, Indazoles pharmacology, Mice, Microsomes, Liver drug effects, Microsomes, Liver metabolism, Enzyme Inhibitors chemistry, Enzyme Inhibitors metabolism, Indazoles chemistry, Indazoles metabolism, Oxidoreductases Acting on CH-CH Group Donors antagonists & inhibitors, Oxidoreductases Acting on CH-CH Group Donors metabolism
- Abstract
Human dihydroorotate dehydrogenase (DHODH), an enzyme in the de novo pyrimidine synthesis pathway, is a target for the treatment of rheumatoid arthritis and multiple sclerosis and is re-emerging as an attractive target for cancer therapy. Here we describe the optimization of recently identified tetrahydroindazoles (HZ) as DHODH inhibitors. Several of the HZ analogues synthesized in this study are highly potent inhibitors of DHODH in an enzymatic assay, while also inhibiting cancer cell growth and viability and activating p53-dependent transcription factor activity in a reporter cell assay. Furthermore, we demonstrate the specificity of the compounds toward the de novo pyrimidine synthesis pathway through supplementation with an excess of uridine. We also show that induction of the DNA damage marker γ-H2AX after DHODH inhibition is preventable by cotreatment with the pan-caspase inhibitor Z-VAD-FMK. Additional solubility and in vitro metabolic stability profiling revealed compound 51 as a favorable candidate for preclinical efficacy studies.
- Published
- 2020
- Full Text
- View/download PDF