2. Academic Validation
  3. Bicyclic Heterocyclic Replacement of an Aryl Amide Leading to Potent and Kinase-Selective Adaptor Protein 2-Associated Kinase 1 Inhibitors

Bicyclic Heterocyclic Replacement of an Aryl Amide Leading to Potent and Kinase-Selective Adaptor Protein 2-Associated Kinase 1 Inhibitors

  • J Med Chem. 2022 Mar 10;65(5):4121-4155. doi: 10.1021/acs.jmedchem.1c01966.
Richard A Hartz 1,  Vijay T Ahuja 1,  Susheel J Nara 2,  C M Vijaya Kumar 2,  Raju K V L P Manepalli 2,  Sarat Kumar Sarvasiddhi 2,  Swarnamba Honkhambe 2,  Vidya Patankar 2,  Bireshwar Dasgupta 1,  Ramkumar Rajamani 3,  Jodi K Muckelbauer 4,  Daniel M Camac 4,  Kaushik Ghosh 2,  Matthew Pokross 4,  Susan E Kiefer 5,  Jeffrey M Brown 6,  Lisa Hunihan 6,  Michael Gulianello 6,  Martin Lewis 6,  Jonathan S Lippy 7,  Neha Surti 7,  Brian D Hamman 8,  Jason Allen 8,  Walter A Kostich 6,  Joanne J Bronson 1,  John E Macor 1,  Carolyn D Dzierba 1
Affiliations

Affiliations

  • 1 Department of Small Molecule Drug Discovery, Bristol Myers Squibb Company, Research and Development, 5 Research Parkway, Wallingford, Connecticut 06492, United States.
  • 2 Biocon-Bristol Myers Squibb Research and Development Center, Biocon Park, Plot No. 2 & 3, Bommasandra Phase IV, Jigani Link Road, Bangalore 560099, India.
  • 3 Department of Molecular Structure and Design, Bristol Myers Squibb Company, Research and Development, 5 Research Parkway, Wallingford, Connecticut 06492, United States.
  • 4 Department of Molecular Structure and Design, Bristol Myers Squibb Company, Research and Development, P.O. Box 5400, Princeton, New Jersey 08543, United States.
  • 5 Department of Protein Science, Bristol Myers Squibb Company, Research and Development, P.O. Box 5400, Princeton, New Jersey 08543, United States.
  • 6 Department of Neuroscience Discovery Biology, Bristol Myers Squibb Company, Research and Development, 5 Research Parkway, Wallingford, Connecticut 06492, United States.
  • 7 Department of Lead Evaluation, Bristol Myers Squibb Company, Research and Development, P.O. Box 5400, Princeton, New Jersey 08543, United States.
  • 8 Lexicon Pharmaceuticals, 8800 Technology Forest Place, The Woodlands, Texas 77381, United States.
PMID: 35171586 DOI: 10.1021/acs.jmedchem.1c01966
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.

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