Development of a bioavailable boron-containing PI-103 Bioisostere,PI-103BE |
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| Affiliation: | 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;1. Department of Pharmacokinetics and Pharmaceutical Technology, Miguel Hernandez University, San Juan de Alicante, 03550 Alicante, Spain;2. Department of Pharmacokinetics and Pharmaceutical Technology, University of Valencia, Av. de Blasco Ibáñez, 13, 46010 Valencia, Spain;3. Molecular Recognition and Technological Development, Polytechnic University −University of Valencia, Camí de Vera, s/n, 46022 Valencia, Spain;4. I3S-Instituto de Investigação e Inovação em Saúde, University of Porto, Rua Alfredo Allen 208, 4200-135 Porto, Portugal;5. INEB-Instituto de Engenharia Biomédica, University of Porto, Rua Alfredo Allen 208, 4200-135 Porto, Portugal;6. CESPU, Instituto de Investigação e Formação Avançada em Ciências e Tecnologias da Saúde, Rua Central da Gandra 1317, 4585-116 Gandra, Portugal;1. Key Laboratory of Biorheological Science and Technology, Ministry of Education, College of Bioengineering, Chongqing University, Chongqing, 400044, China;2. Southwest Pharmaceutical.Co. Ltd., Chongqing, 400038, China;1. Department of Chemistry, University of Liverpool, Crown Street, Liverpool L69 7ZD, UK;2. Department of Molecular and Clinical Pharmacology, University of Liverpool, 70 Pembroke Place, Liverpool L69 3GF, UK;3. ViiV Healthcare, Five Moore Drive, Research Triangle Park, NC, USA;4. Pfizer, 235 East 42nd Street, New York, NY, USA;5. ViiV Healthcare UK Limited, 980 Great West Road, Brentford, Middlesex TW8 9GS, UK;1. Nutrition Research Division, Bureau of Nutritional Sciences, Food Directorate, Health Products and Food Branch, Health Canada, Ottawa, Ontario, Canada;2. Department of Biochemistry, Microbiology and Immunology, University of Ottawa, Ottawa, Ontario, Canada |
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| 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. |
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| Keywords: | PI-103 bioisosteres Boron-containing compound Synthesis Pharmacokinetics Bioavailability |
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