2. Academic Validation
  3. Discovery and Optimization of Biaryl Alkyl Ethers as a Novel Class of Highly Selective, CNS-Penetrable, and Orally Active Adaptor Protein-2-Associated Kinase 1 (AAK1) Inhibitors for the Potential Treatment of Neuropathic Pain

Discovery and Optimization of Biaryl Alkyl Ethers as a Novel Class of Highly Selective, CNS-Penetrable, and Orally Active Adaptor Protein-2-Associated Kinase 1 (AAK1) Inhibitors for the Potential Treatment of Neuropathic Pain

  • J Med Chem. 2022 Mar 24;65(6):4534-4564. doi: 10.1021/acs.jmedchem.1c02132.
Guanglin Luo 1,  Ling Chen 1,  Walter A Kostich 2,  Brian Hamman 3,  Jason Allen 3,  Amy Easton 2,  Clotilde Bourin 2,  Michael Gulianello 2,  Jonathan Lippy 4,  Susheel Nara 5,  Sreenivasulu Naidu Pattipati 5,  Kumaran Dandapani 5,  Manoj Dokania 5,  Pradeep Vattikundala 5,  Vivek Sharma 5,  Saravanan Elavazhagan 5,  Manoj Kumar Verma 5,  Manish Lal Das 5,  Santosh Wagh 5,  Anand Balakrishnan 6,  Benjamin M Johnson 6,  Kenneth S Santone 6,  George Thalody 7,  Rex Denton 7,  Hariharan Saminathan 5,  Vinay K Holenarsipur 5,  Anoop Kumar 5,  Abhijith Rao 5,  Siva Prasad Putlur 5,  Sarat Kumar Sarvasiddhi 5,  Ganesh Shankar 5,  Justin V Louis 5,  Manjunath Ramarao 5,  Charles M Conway 2,  Yu-Wen Li 2,  Rick Pieschl 2,  Yuan Tian 2,  Yang Hong 2,  Linda Bristow 2,  Charles F Albright 2,  Joanne J Bronson 1,  John E Macor 1,  Carolyn D Dzierba 1
Affiliations

Affiliations

  • 1 Department of Neuroscience Chemistry, Bristol-Myers Squibb Company, 5 Research Parkway, Wallingford, Connecticut 06492, United States.
  • 2 Department of Neuroscience Discovery Biology, Bristol-Myers Squibb Company, 5 Research Parkway, Wallingford, Connecticut 06492, United States.
  • 3 Lexicon Pharmaceuticals, 8800 Technology Forest Place, The Woodlands, Texas 77381, United States.
  • 4 Department of Lead Evaluation, Bristol Myers Squibb Company, Route 206 & Province Line Rd, Princeton, New Jersey 08543, United States.
  • 5 Biocon-Bristol Myers Squibb Research and Development Centre, Biocon Park, Plot No. 2 & 3, Bommasandra Phase IV, Jigani Link Road, Bangalore 560099, India.
  • 6 Department of Pharmaceutical Candidate Optimization, Bristol Myers Squibb Company, 5 Research Parkway, Wallingford, Connecticut 06492, United States.
  • 7 Discovery Toxicology, Bristol Myers Squibb Company, Route 206 & Province Line Rd, Princeton, New Jersey 08543, United States.
PMID: 35261239 DOI: 10.1021/acs.jmedchem.1c02132
Abstract

Recent mouse knockout studies identified adapter protein-2-associated kinase 1 (AAK1) as a viable target for treating neuropathic pain. BMS-986176/LX-9211 (4), as a highly selective, CNS-penetrable, and potent AAK1 Inhibitor, has advanced into phase II human trials. On exploring the structure-activity relationship (SAR) around this biaryl alkyl ether chemotype, several additional compounds were found to be highly selective and potent AAK1 inhibitors with good druglike properties. Among these, compounds 43 and 58 showed very good efficacy in two neuropathic pain rat models and had excellent CNS penetration and spinal cord target engagement. Both compounds also exhibited favorable physicochemical and oral pharmacokinetic (PK) properties. Compound 58, a central pyridine isomer of BMS-986176/LX-9211 (4), was 4-fold more potent than 4 in vitro and showed lower plasma exposure needed to achieve similar efficacy compared to 4 in the CCI rat model. However, both 43 and 58 showed an inferior preclinical toxicity profile compared to 4.

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