Optimization of hERG and Pharmacokinetic Properties for Basic Dihydro-8 H -purin-8-one Inhibitors of DNA-PK.

Autor: Goldberg FW; Oncology R&D, AstraZeneca, Cambridge CB2 0AA, U.K., Ting AKT; Oncology R&D, AstraZeneca, Cambridge CB2 0AA, U.K., Beattie D; Oncology R&D, AstraZeneca, Cambridge CB2 0AA, U.K., Lamont GM; Oncology R&D, AstraZeneca, Cambridge CB2 0AA, U.K., Fallan C; Oncology R&D, AstraZeneca, Cambridge CB2 0AA, U.K., Finlay MRV; Oncology R&D, AstraZeneca, Cambridge CB2 0AA, U.K., Williamson B; Oncology R&D, AstraZeneca, Cambridge CB2 0AA, U.K., Schimpl M; Oncology R&D, AstraZeneca, Cambridge CB2 0AA, U.K., Harmer AR; Clinical Pharmacology and Safety Sciences, R&D, AstraZeneca, Cambridge CB2 0AA, U.K., Adeyemi OB; Clinical Pharmacology and Safety Sciences, R&D, AstraZeneca, Cambridge CB2 0AA, U.K., Nordell P; Biopharmaceuticals R&D, AstraZeneca, 431 50 Gothenburg, Sweden., Cronin AS; Clinical Pharmacology and Safety Sciences, R&D, AstraZeneca, Cambridge CB2 0AA, U.K., Vazquez-Chantada M; Discovery Sciences, R&D, AstraZeneca, Cambridge CB2 0AA, U.K., Barratt D; Discovery Sciences, R&D, AstraZeneca, Cambridge CB2 0AA, U.K., Ramos-Montoya A; Oncology R&D, AstraZeneca, Cambridge CB2 0AA, U.K., Cadogan EB; Oncology R&D, AstraZeneca, Cambridge CB2 0AA, U.K., Davies BR; Oncology R&D, AstraZeneca, Cambridge CB2 0AA, U.K.
Jazyk: angličtina
Zdroj: ACS medicinal chemistry letters [ACS Med Chem Lett] 2022 Jul 07; Vol. 13 (8), pp. 1295-1301. Date of Electronic Publication: 2022 Jul 07 (Print Publication: 2022).
DOI: 10.1021/acsmedchemlett.2c00172
Abstrakt: The DNA-PK complex is activated by double-strand DNA breaks and regulates the non-homologous end-joining repair pathway; thus, targeting DNA-PK by inhibiting the DNA-PK catalytic subunit (DNA-PKcs) is potentially a useful therapeutic approach for oncology. A previously reported series of neutral DNA-PKcs inhibitors were modified to incorporate a basic group, with the rationale that increasing the volume of distribution while maintaining good metabolic stability should increase the half-life. However, adding a basic group introduced hERG activity, and basic compounds with modest hERG activity (IC 50 = 10-15 μM) prolonged QTc (time from the start of the Q wave to the end of the T wave, corrected by heart rate) in an anaesthetized guinea pig cardiovascular model. Further optimization was necessary, including modulation of p K a , to identify compound 18 , which combines low hERG activity (IC 50 = 75 μM) with excellent kinome selectivity and favorable pharmacokinetic properties.
Competing Interests: The authors declare no competing financial interest.
(© 2022 American Chemical Society.)
Databáze: MEDLINE
Externí odkaz: