Document Report Card

ID: ALA1671825

Journal: ACS Med Chem Lett

Title: Synthesis and in Vitro and in Vivo Evaluation of Phosphoinositide-3-kinase Inhibitors.

Authors: Burger MT, Knapp M, Wagman A, Ni ZJ, Hendrickson T, Atallah G, Zhang Y, Frazier K, Verhagen J, Pfister K, Ng S, Smith A, Bartulis S, Merrit H, Weismann M, Xin X, Haznedar J, Voliva CF, Iwanowicz E, Pecchi S.

Abstract: Phospoinositide-3-kinases (PI3K) are important oncology targets due to the deregulation of this signaling pathway in a wide variety of human cancers. A series of 2-morpholino, 4-substituted, 6-(3-hydroxyphenyl) pyrimidines have been reported as potent inhibitors of PI3Ks. Herein, we describe the structure-guided optimization of these pyrimidines with a focus on replacing the phenol moiety, while maintaining potent target inhibition and improving in vivo properties. A series of 2-morpholino, 4-substituted, 6-heterocyclic pyrimidines, which potently inhibit PI3K, were discovered. Within this series a compound, 17, was identified with suitable pharmacokinetic (PK) properties, which allowed for the establishment of a PI3K PK/pharmacodynamic-efficacy relationship as determined by in vivo inhibition of AKT(Ser473) phosphorylation and tumor growth inhibition in a mouse A2780 tumor xenograft model.

CiteXplore: 24900252

DOI: 10.1021/ml1001932