1. Bicyclic Heterocyclic Replacement of an Aryl Amide Leading to Potent and Kinase-Selective Adaptor Protein 2-Associated Kinase 1 Inhibitors.
- Author
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Hartz RA, Ahuja VT, Nara SJ, Kumar CMV, Manepalli RKVLP, Sarvasiddhi SK, Honkhambe S, Patankar V, Dasgupta B, Rajamani R, Muckelbauer JK, Camac DM, Ghosh K, Pokross M, Kiefer SE, Brown JM, Hunihan L, Gulianello M, Lewis M, Lippy JS, Surti N, Hamman BD, Allen J, Kostich WA, Bronson JJ, Macor JE, and Dzierba CD
- Subjects
- Amides pharmacology, Amides therapeutic use, Animals, Protein Kinase Inhibitors pharmacology, Protein Kinase Inhibitors therapeutic use, Quinazolines therapeutic use, Structure-Activity Relationship, Neuralgia drug therapy, Quinolines pharmacology, Quinolines therapeutic use
- Abstract
Adaptor protein 2-associated kinase 1 (AAK1) is a serine/threonine kinase that was identified as a therapeutic target for the potential treatment of neuropathic pain. Inhibition of AAK1 in the central nervous system, particularly within the spinal cord, was found to be the relevant site for achieving an antinociceptive effect. We previously reported that compound 7 is a brain-penetrant, AAK1 inhibitor that showed efficacy in animal models for neuropathic pain. One approach we took to improve upon the potency of 7 involved tying the amide back into the neighboring phenyl ring to form a bicyclic heterocycle. Investigation of the structure-activity relationships (SARs) of substituents on the resultant quinazoline and quinoline ring systems led to the identification of ( S )-31 , a brain-penetrant, AAK1-selective inhibitor with improved enzyme and cellular potency compared to 7 . The synthesis, SAR, and in vivo evaluation of a series of quinazoline and quinoline-based AAK1 inhibitors are described herein.
- Published
- 2022
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