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

Bioorg Med Chem Lett. 2020 Jul 15;30(14):127258. doi: 10.1016/j.bmcl.2020.127258.

Lan Luo ¹, Qiu Zhong ², Shanchun Guo ², Changde Zhang ², Qiang Zhang ², Shilong Zheng ³, Ling He ⁴, Guangdi Wang ⁵

Affiliations

1 Key Laboratory of Drug-Targeting and Drug Delivery System of the Education Ministry, Sichuan Engineering Laboratory for Plant-Sourced Drug and Sichuan Research Center for Drug Precision Industrial Technology, Department of Medicinal Chemistry, West China School of Pharmacy, Sichuan University, Chengdu, Sichuan 610041, China.
2 RCMI Cancer Research Center and Department of Chemistry, Xavier University of Louisiana, New Orleans, LA 70125, USA.
3 RCMI Cancer Research Center and Department of Chemistry, Xavier University of Louisiana, New Orleans, LA 70125, USA. Electronic address: szheng@xula.edu.
4 Key Laboratory of Drug-Targeting and Drug Delivery System of the Education Ministry, Sichuan Engineering Laboratory for Plant-Sourced Drug and Sichuan Research Center for Drug Precision Industrial Technology, Department of Medicinal Chemistry, West China School of Pharmacy, Sichuan University, Chengdu, Sichuan 610041, China. Electronic address: heling2012@scu.edu.cn.
5 RCMI Cancer Research Center and Department of Chemistry, Xavier University of Louisiana, New Orleans, LA 70125, USA. Electronic address: gwang@xula.edu.

PMID: 32527558 DOI: 10.1016/j.bmcl.2020.127258

Abstract

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.

Keywords

Bioavailability; Boron-containing compound; PI-103 bioisosteres; Pharmacokinetics; Synthesis.

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