Discovery of pyrrolo[2,1- f ][1,2,4]triazine-based inhibitors of adaptor protein 2-associated kinase 1 for the treatment of pain.

Autor: Dzierba CD; Small Molecule Drug Discovery, Bristol Myers Squibb, Research and Development, 250 Water St, Cambridge, MA 02141 USA., Dasgupta B; Department of Neuroscience Chemistry, Bristol Myers Squibb, Bristol Myers Squibb Company, Research and Development, 5 Research Parkway, Wallingford, CT 06492 USA., Karageorge G; Department of Neuroscience Chemistry, Bristol Myers Squibb, Bristol Myers Squibb Company, Research and Development, 5 Research Parkway, Wallingford, CT 06492 USA., Kostich W; Department of Neuroscience Biology, Bristol Myers Squibb, Bristol Myers Squibb Company, Research and Development, 5 Research Parkway, Wallingford, CT 06492 USA., Hamman B; Lexicon Pharmaceuticals 8800 Technology Forest Place, The Woodlands, TX 77381 USA., Allen J; Lexicon Pharmaceuticals 8800 Technology Forest Place, The Woodlands, TX 77381 USA., Esposito KM; Department of Leads Discovery and Optimization, Bristol Myers Squibb, Bristol Myers Squibb Company, Research and Development, 5 Research Parkway, Wallingford, CT 06492 USA., Padmanabha R; Department of Leads Discovery and Optimization, Bristol Myers Squibb, Research and Development, P.O. Box 5400, Princeton, NJ 08543 USA., Grace J; Department of Pharmaceutical Candidate Optimization, Bristol Myers Squibb, Bristol Myers Squibb Company, Research and Development, 5 Research Parkway, Wallingford, CT 06492 USA., Lentz K; Department of Pharmaceutical Candidate Optimization, Bristol Myers Squibb, Bristol Myers Squibb Company, Research and Development, 5 Research Parkway, Wallingford, CT 06492 USA., Morrison J; Department of Pharmaceutical Candidate Optimization, Bristol Myers Squibb, Bristol Myers Squibb Company, Research and Development, 5 Research Parkway, Wallingford, CT 06492 USA., Morgan D; Department of Pharmaceutical Candidate Optimization, Bristol Myers Squibb, Bristol Myers Squibb Company, Research and Development, 5 Research Parkway, Wallingford, CT 06492 USA., Easton A; Department of Neuroscience Biology, Bristol Myers Squibb, Bristol Myers Squibb Company, Research and Development, 5 Research Parkway, Wallingford, CT 06492 USA., Bourin C; Department of Neuroscience Biology, Bristol Myers Squibb, Bristol Myers Squibb Company, Research and Development, 5 Research Parkway, Wallingford, CT 06492 USA., Browning MR; Department of Pharmaceutical Candidate Optimization, Bristol Myers Squibb, Bristol Myers Squibb Company, Research and Development, 5 Research Parkway, Wallingford, CT 06492 USA., Rajamani R; Department of Molecular Structure and Design, Bristol Myers Squibb, Bristol Myers Squibb Company, Research and Development, 5 Research Parkway, Wallingford, CT 06492 USA., Good A; Department of Molecular Structure and Design, Bristol Myers Squibb, Bristol Myers Squibb Company, Research and Development, 5 Research Parkway, Wallingford, CT 06492 USA., Parker DD; Department of Pharmaceutical Candidate Optimization, Bristol Myers Squibb, Bristol Myers Squibb Company, Research and Development, 5 Research Parkway, Wallingford, CT 06492 USA., Muckelbauer JK; Department of Molecular Structure and Design, Bristol Myers Squibb, Research and Development, P.O. Box 5400, Princeton, NJ 08543 USA., Khan J; Department of Molecular Structure and Design, Bristol Myers Squibb, Research and Development, P.O. Box 5400, Princeton, NJ 08543 USA., Camac D; Department of Molecular Structure and Design, Bristol Myers Squibb, Research and Development, P.O. Box 5400, Princeton, NJ 08543 USA., Ghosh K; Biocon-Bristol Myers Squibb Research and Development Center, Biocon Park, Plot No. 2 & 3, Bommasandra Phase IV, Jigani Link Road, Bangalore, 560099 India., Halan V; Biocon-Bristol Myers Squibb Research and Development Center, Biocon Park, Plot No. 2 & 3, Bommasandra Phase IV, Jigani Link Road, Bangalore, 560099 India., Lippy JS; Department of Leads Discovery and Optimization, Bristol Myers Squibb, Research and Development, P.O. Box 5400, Princeton, NJ 08543 USA., Santone KS; Department of Pharmaceutical Candidate Optimization, Bristol Myers Squibb, Bristol Myers Squibb Company, Research and Development, 5 Research Parkway, Wallingford, CT 06492 USA., Denton RR; Department of Pharmaceutical Candidate Optimization, Bristol Myers Squibb, Research and Development, 250 Water St, Cambridge, MA 02141 USA., Westphal R; Department of Neuroscience Biology, Bristol Myers Squibb, Bristol Myers Squibb Company, Research and Development, 5 Research Parkway, Wallingford, CT 06492 USA., Bristow LJ; Department of Neuroscience Biology, Bristol Myers Squibb, Bristol Myers Squibb Company, Research and Development, 5 Research Parkway, Wallingford, CT 06492 USA., Conway CM; Department of Neuroscience Biology, Bristol Myers Squibb, Bristol Myers Squibb Company, Research and Development, 5 Research Parkway, Wallingford, CT 06492 USA., Bronson JJ; Small Molecule Drug Discovery, Bristol Myers Squibb, Research and Development, 250 Water St, Cambridge, MA 02141 USA., Macor JE; Department of Neuroscience Chemistry, Bristol Myers Squibb, Bristol Myers Squibb Company, Research and Development, 5 Research Parkway, Wallingford, CT 06492 USA.
Jazyk: angličtina
Zdroj: Medicinal chemistry research : an international journal for rapid communications on design and mechanisms of action of biologically active agents [Med Chem Res] 2023 Jun 03, pp. 1-7. Date of Electronic Publication: 2023 Jun 03.
DOI: 10.1007/s00044-023-03079-x
Abstrakt: Adaptor protein 2-associated kinase 1 (AAK1) is a member of the Ark1/Prk1 family of serine/threonine kinases and plays a role in modulating receptor endocytosis. AAK1 was identified as a potential therapeutic target for the treatment of neuropathic pain when it was shown that AAK1 knock out (KO) mice had a normal response to the acute pain phase of the mouse formalin model, but a reduced response to the persistent pain phase. Herein we report our early work investigating a series of pyrrolo[2,1- f ][1,2,4]triazines as part of our efforts to recapitulate this KO phenotype with a potent, small molecule inhibitor of AAK1. The synthesis, structure-activity relationships (SAR), and in vivo evaluation of these AAK1 inhibitors is described.
Competing Interests: Conflict of interestThe authors declare no competing interests.
(© The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature 2023.)
Databáze: MEDLINE
Externí odkaz: