Design and Development of a Macrocyclic Series Targeting
Phosphoinositide 3‑Kinase δ
Posted on 2020-06-18 - 15:05
A macrocyclization
approach has been explored on a series of benzoxazine
phosphoinositide 3-kinase δ inhibitors, resulting in compounds
with improved potency, permeability, and in vivo clearance
while maintaining good solubility. The thermodynamics of binding was
explored via surface plasmon resonance, and the binding of lead macrocycle 19 was found to be almost exclusively entropically driven
compared with progenitor 18, which demonstrated both
enthalpic and entropic contributions. The pharmacokinetics of macrocycle 19 was also explored in vivo, where it showed
reduced clearance when compared with the progenitor 18. This work adds to the growing body of evidence that macrocyclization
could provide an alternative and complementary approach to the design
of small-molecule inhibitors, with the potential to deliver differentiated
properties.
CITE THIS COLLECTION
DataCiteDataCite
3 Biotech3 Biotech
3D Printing in Medicine3D Printing in Medicine
3D Research3D Research
3D-Printed Materials and Systems3D-Printed Materials and Systems
4OR4OR
AAPG BulletinAAPG Bulletin
AAPS OpenAAPS Open
AAPS PharmSciTechAAPS PharmSciTech
Abhandlungen aus dem Mathematischen Seminar der Universität HamburgAbhandlungen aus dem Mathematischen Seminar der Universität Hamburg
ABI Technik (German)ABI Technik (German)
Academic MedicineAcademic Medicine
Academic PediatricsAcademic Pediatrics
Academic PsychiatryAcademic Psychiatry
Academic QuestionsAcademic Questions
Academy of Management DiscoveriesAcademy of Management Discoveries
Academy of Management JournalAcademy of Management Journal
Academy of Management Learning and EducationAcademy of Management Learning and Education
Academy of Management PerspectivesAcademy of Management Perspectives
Academy of Management ProceedingsAcademy of Management Proceedings
Academy of Management ReviewAcademy of Management Review
Spencer, Jonathan
A.; Baldwin, Ian R.; Barton, Nick; Chung, Chun-Wa; Convery, Máire A.; Edwards, Christopher D.; et al. (2020). Design and Development of a Macrocyclic Series Targeting
Phosphoinositide 3‑Kinase δ. ACS Publications. Collection. https://doi.org/10.1021/acsmedchemlett.0c00061