Modification of a dihydropyrrolopyrimidine phosphoinositide 3-kinase (PI3K) inhibitor to improve oral bioavailability

• Published in: Bioorganic & medicinal chemistry Vol. 23; no. 24; pp. 7650 - 7660
• Main Authors: Kawada, Hatsuo, Ebiike, Hirosato, Tsukazaki, Masao, Yamamoto, Shun, Koyama, Kohei, Nakamura, Mitsuaki, Morikami, Kenji, Yoshinari, Kiyoshi, Yoshida, Miyuki, Ogawa, Kotaro, Shinma, Nobuo, Tsukuda, Takuo, Ohwada, Jun
• Format: Journal Article
• Language: English
• Published: OXFORD Elsevier Ltd 15.12.2015; Elsevier
• Subjects: Administration, Oral; Animals; Biochemistry & Molecular Biology; Biological Availability; Cancer; Chemistry; Chemistry, Medicinal; Chemistry, Organic; Female; Humans; Life Sciences & Biomedicine; Liver microsomal stability; Macaca fascicularis; Male; Mice, Inbred BALB C; Microsomes, Liver - metabolism; Molecular planarity; Permeability; Pharmacokinetic profile; Pharmacology & Pharmacy; Phosphatidylinositol 3-Kinases - antagonists & inhibitors; Physical Sciences; PI3K; Protein Kinase Inhibitors - administration & dosage; Protein Kinase Inhibitors - chemistry; Protein Kinase Inhibitors - metabolism; Protein Kinase Inhibitors - pharmacokinetics; Pyrimidines - administration & dosage; Pyrimidines - chemistry; Pyrimidines - metabolism; Pyrimidines - pharmacokinetics; Pyrroles - administration & dosage; Pyrroles - chemistry; Pyrroles - metabolism; Pyrroles - pharmacokinetics; Science & Technology; Solubility; Pharmacokinetic profile; Liver microsomal stability; Molecular planarity; PI3K; Solubility; Permeability; Cancer; PATHWAY; MUTATIONS
• ISSN: 0968-0896; 1464-3391
• DOI: 10.1016/j.bmc.2015.11.009

[Display omitted] Phosphoinositide 3-kinase (PI3K) is activated in various human cancer cells and well known as a cancer therapy target. We previously reported a dihydropyrrolopyrimidine derivative as a highly potent PI3K inhibitor that has strong tumor growth inhibition in a xenograft model. In this report, we describe further optimization to improve its bioavailability.