Design and Development of a Macrocyclic Series Targeting Phosphoinositide 3-Kinase δ.

Autor:	Spencer JA; GSK Medicines Research Centre, Gunnels Wood Road, Stevenage SG1 2NY, United Kingdom.; Department of Pure and Applied Chemistry, University of Strathclyde, 295 Cathedral Street, Glasgow G1 1XL, United Kingdom., Baldwin IR; GSK Medicines Research Centre, Gunnels Wood Road, Stevenage SG1 2NY, United Kingdom., Barton N; GSK Medicines Research Centre, Gunnels Wood Road, Stevenage SG1 2NY, United Kingdom., Chung CW; GSK Medicines Research Centre, Gunnels Wood Road, Stevenage SG1 2NY, United Kingdom., Convery MA; GSK Medicines Research Centre, Gunnels Wood Road, Stevenage SG1 2NY, United Kingdom., Edwards CD; GSK Medicines Research Centre, Gunnels Wood Road, Stevenage SG1 2NY, United Kingdom., Jamieson C; Department of Pure and Applied Chemistry, University of Strathclyde, 295 Cathedral Street, Glasgow G1 1XL, United Kingdom., Mallett DN; GSK Medicines Research Centre, Gunnels Wood Road, Stevenage SG1 2NY, United Kingdom., Rowedder JE; GSK Medicines Research Centre, Gunnels Wood Road, Stevenage SG1 2NY, United Kingdom., Rowland P; GSK Medicines Research Centre, Gunnels Wood Road, Stevenage SG1 2NY, United Kingdom., Thomas DA; GSK Medicines Research Centre, Gunnels Wood Road, Stevenage SG1 2NY, United Kingdom., Hardy CJ; GSK Medicines Research Centre, Gunnels Wood Road, Stevenage SG1 2NY, United Kingdom.
Jazyk:	angličtina
Zdroj:	ACS medicinal chemistry letters [ACS Med Chem Lett] 2020 Jun 03; Vol. 11 (7), pp. 1386-1391. Date of Electronic Publication: 2020 Jun 03 (Print Publication: 2020).
DOI:	10.1021/acsmedchemlett.0c00061
Abstrakt:	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. Competing Interests: The authors declare the following competing financial interest(s): All authors except J.A.S and C.J. were employees of GlaxoSmithKline at the time the work was carried out. (Copyright © 2020 American Chemical Society.)
Databáze:	MEDLINE
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