دورية أكاديمية
Parallel Optimisation of Potency and Pharmacokinetics Leading to the Discovery of a Pyrrole Carboxamide ERK5 Kinase Domain Inhibitor
| العنوان: | Parallel Optimisation of Potency and Pharmacokinetics Leading to the Discovery of a Pyrrole Carboxamide ERK5 Kinase Domain Inhibitor |
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| المؤلفون: | Miller, Duncan C, Reuillon, Tristan, Molyneux, Lauren, Blackburn, Timothy, Cook, Simon J, Edwards, Noel, Endicott, Jane A, Golding, Bernard T, Griffin, Roger J, Hardcastle, Ian, Harnor, Suzannah J, Heptinstall, Amy, Lochhead, Pamela, Martin, Mathew P, Martin, Nick C, Myers, Stephanie, Newell, David R, Noble, Richard A, Phillips, Nicole, Rigoreau, Laurent, Thomas, Huw, Tucker, Julie A, Wang, Lan-Zhen, Waring, Michael J, Wong, Ai-Ching, Wedge, Stephen R, Noble, Martin E, Cano, Celine |
| بيانات النشر: | American Chemical Society |
| سنة النشر: | 2022 |
| المجموعة: | University of Sunderland: SUnderland REpository (SURE) |
| مصطلحات موضوعية: | Chemistry |
| الوصف: | The non-classical extracellular signal-related kinase 5 (ERK5) mitogen-activated protein kinase pathway has been implicated in increased cellular proliferation, migration, survival and angiogenesis, hence ERK5 inhibition may be an attractive approach for cancer treatment. However, development of selective ERK5 inhibitors has been challenging. Previously, we described the development of a pyrrole-carboxamide high-throughput screening hit into a selective, submicromolar inhibitor of ERK5 kinase activity. Improvement in the ERK5 potency was necessary for the identification of a tool ERK5 inhibitor for target validation studies. Herein, we describe the optimisation of this series to identify nanomolar pyrrole carboxamide inhibitors of ERK5 incorporating a basic centre, which suffered from poor oral bioavailability. Parallel optimisation of potency and in vitro pharmacokinetic parameters led to the identification of a non-basic pyrazole analogue with an optimal balance of ERK5 inhibition and oral exposure. |
| نوع الوثيقة: | article in journal/newspaper |
| وصف الملف: | application/pdf |
| اللغة: | English |
| العلاقة: | http://sure.sunderland.ac.uk/id/eprint/14709/8/acs.jmedchem.1c01756.pdfTest; Miller, Duncan C , Reuillon, Tristan , Molyneux, Lauren , Blackburn, Timothy , Cook, Simon J , Edwards, Noel , Endicott, Jane A , Golding, Bernard T , Griffin, Roger J , Hardcastle, Ian , Harnor, Suzannah J , Heptinstall, Amy , Lochhead, Pamela , Martin, Mathew P , Martin, Nick C , Myers, Stephanie , Newell, David R , Noble, Richard A , Phillips, Nicole , Rigoreau, Laurent , Thomas, Huw , Tucker, Julie A , Wang, Lan-Zhen , Waring, Michael J , Wong, Ai-Ching , Wedge, Stephen R , Noble, Martin E and Cano, Celine (2022) Parallel Optimisation of Potency and Pharmacokinetics Leading to the Discovery of a Pyrrole Carboxamide ERK5 Kinase Domain Inhibitor. Journal of Medicinal Chemistry, 65 (9). pp. 6513-6540. ISSN 0022-2623 |
| DOI: | 10.1021/acs.jmedchem.1c01756 |
| الإتاحة: | http://sure.sunderland.ac.uk/id/eprint/14709Test/ http://sure.sunderland.ac.uk/id/eprint/14709/8/acs.jmedchem.1c01756.pdfTest |
| حقوق: | cc_by_4 |
| رقم الانضمام: | edsbas.F10DA7BC |
| قاعدة البيانات: | BASE |
| DOI: | 10.1021/acs.jmedchem.1c01756 |
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