Structure-Based Drug Design of Novel Potent and Selective Tetrahydropyrazolo[1,5- a ]pyrazines as ATR Inhibitors
Journal Article
·
· ACS Medicinal Chemistry Letters
A saturation strategy focused on improving the selectivity and physicochemical properties of ATR inhibitor HTS hit 1 led to a novel series of highly potent and selective tetrahydropyrazolo[1,5-a]pyrazines. Use of PI3Kα mutants as ATR crystal structure surrogates was instrumental in providing cocrystal structures to guide the medicinal chemistry designs. Detailed DMPK studies involving cyanide and GSH as trapping agents during microsomal incubations, in addition to deuterium-labeled compounds as mechanistic probes uncovered the molecular basis for the observed CYP3A4 TDI in the series.
- Research Organization:
- Advanced Photon Source (APS), Argonne National Laboratory (ANL), Argonne, IL (US)
- Sponsoring Organization:
- USDOE Office of Science (SC)
- OSTI ID:
- 1405002
- Journal Information:
- ACS Medicinal Chemistry Letters, Journal Name: ACS Medicinal Chemistry Letters Journal Issue: 1 Vol. 6; ISSN 1948-5875
- Publisher:
- American Chemical Society (ACS)
- Country of Publication:
- United States
- Language:
- ENGLISH
Similar Records
Development of Potent and Selective Pyrazolopyrimidine IRAK4 Inhibitors
Discovery of 3-morpholino-imidazole[1,5- a ]pyrazine BTK inhibitors for rheumatoid arthritis
Identification of Selective Dual ROCK1 and ROCK2 Inhibitors Using Structure-Based Drug Design
Journal Article
·
Mon May 13 00:00:00 EDT 2019
· Journal of Medicinal Chemistry
·
OSTI ID:1544868
Discovery of 3-morpholino-imidazole[1,5- a ]pyrazine BTK inhibitors for rheumatoid arthritis
Journal Article
·
Tue Aug 01 00:00:00 EDT 2017
· Bioorganic and Medicinal Chemistry Letters
·
OSTI ID:1404954
Identification of Selective Dual ROCK1 and ROCK2 Inhibitors Using Structure-Based Drug Design
Journal Article
·
Thu Nov 01 00:00:00 EDT 2018
· Journal of Medicinal Chemistry
·
OSTI ID:1499728