Utilizing structure based drug design and metabolic soft spot identification to optimize the in vitro potency and in vivo pharmacokinetic properties leading to the discovery of novel reversible Bruton’s tyrosine kinase inhibitors
| Autor: | Ella Negrou, Tracy J. Jenkins, Mark T. Cancilla, Douglas Marcotte, Minna Bui, Wenjin Yang, Brian T. Hopkins, Mukush Lulla, Daniel A. Erlanson, Eris Bame, Patrick Conlon, Stig Hansen, Elisabeth Mertsching, Tonika Bohnert, Noah Bell, Daniel Scott, Marx Isaac, Stacey A. Heumann, Junfa Fan, Ying Liu, Tarra Fuchs-Knotts, Laura Silvian, Chuck Gua, YuTing Liu, Jon K. Bowden-Verhoek, Michael J. Romanowski, Bob McDowell, Patrick Cullen, Min Zhong |
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| Rok vydání: | 2021 |
| Předmět: |
Drug
media_common.quotation_subject Clinical Biochemistry Pharmaceutical Science Drug resistance 01 natural sciences Biochemistry Structure-Activity Relationship immune system diseases In vivo hemic and lymphatic diseases Drug Discovery Agammaglobulinaemia Tyrosine Kinase Humans Bruton's tyrosine kinase Potency Kinome Protein Kinase Inhibitors Molecular Biology media_common Dose-Response Relationship Drug Molecular Structure biology 010405 organic chemistry Chemistry Organic Chemistry In vitro 0104 chemical sciences 010404 medicinal & biomolecular chemistry biology.protein Cancer research Molecular Medicine Tyrosine kinase |
| Zdroj: | Bioorganic & Medicinal Chemistry. 44:116275 |
| ISSN: | 0968-0896 |
| Popis: | Bruton's tyrosine kinase (BTK) is an essential node on the BCR signaling in B cells, which are clinically validated to play a critical role in B-cell lymphomas and various auto-immune diseases such as Multiple Sclerosis (MS), Pemphigus, and rheumatoid arthritis (RA). Although non-selective irreversible BTK inhibitors have been approved for oncology, due to the emergence of drug resistance in B-cell lymphoma associated with covalent inhibitor, there an unmet medical need to identify reversible, selective, potent BTK inhibitor as viable therapeutics for patients. Herein, we describe the identification of Hits and subsequence optimization to improve the physicochemical properties, potency and kinome selectivity leading to the discovery of a novel class of BTK inhibitors. Utilizing Met ID and structure base design inhibitors were synthesized with increased in vivo metabolic stability and oral exposure in rodents suitable for advancing to lead optimization. |
| Databáze: | OpenAIRE |
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