Development of a bioavailable boron-containing PI-103 Bioisostere, PI-103BE

• Published in: Bioorganic & medicinal chemistry letters 2020-07, Vol.30 (14), p.127258-127258, Article 127258
• Main Authors: Luo, Lan, Zhong, Qiu, Guo, Shanchun, Zhang, Changde, Zhang, Qiang, Zheng, Shilong, He, Ling, Wang, Guangdi
• Format: Article
• Language: English
• Subjects: Bioavailability; Boron-containing compound; Pharmacokinetics; PI-103 bioisosteres; Synthesis
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2020.127258

Novel PI-103 bioisostere, PI-103BE (9), displays higher bioavailability than PI 103 (7) in vivo. [Display omitted] PI-103 (7) is a potent dual phosphatidylinositol 3-kinase (PI3K)/mTOR inhibitor, but its rapid in vivo metabolism hinders its further clinical development. To improve the bioavailability of PI-103, we designed and synthesized a PI-103 bioisostere, PI-103BE (9) in which the phenolic hydroxyl group of PI-103 was replaced by a boronate, a structural modification known to enhance bioavailability of molecules containing phenolic hydroxyl moieties. In cell culture, PI-103BE is partially converted to its corresponding boronic acid (10) and to a lesser extent the active ingredient, PI-103. This mixture contributes to the in vitro activity of 9 that shows reduced potency compared to the parent compound. When administered to mice by oral gavage, 9 displays a significantly improved pharmacokinetic profile compared to PI-103, which shows no oral bioavailability at the same dose. Drug exposure of 9 as measured by the area under curve (AUC) value is 88.2 ng/mL*h for 7 and 8879.9 ng/mL*h for 10. When given by intraperitoneal injection (IP), the prodrug afforded an AUC of 32.3 ng/mL*h for 7 and 400.9 ng/mL*h for 10, compared to 9.7 ng/mL*h from PI-103 injection. In plasma from both pharmacokinetic studies, 9 is fully converted to 10 and 7, with the boronic acid metabolite (10) displaying antiproliferative activities comparable to 9, but weaker than 7. The boronic bioisostere of PI-103 thus offers an improved bioavailability that could be translated to in vivo efficacy of PI-103.