TY - JOUR
T1 - 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
AU - Luo, Guanglin
AU - Chen, Ling
AU - Kostich, Walter A.
AU - Hamman, Brian
AU - Allen, Jason
AU - Easton, Amy
AU - Bourin, Clotilde
AU - Gulianello, Michael
AU - Lippy, Jonathan
AU - Nara, Susheel
AU - Pattipati, Sreenivasulu Naidu
AU - Dandapani, Kumaran
AU - Dokania, Manoj
AU - Vattikundala, Pradeep
AU - Sharma, Vivek
AU - Elavazhagan, Saravanan
AU - Verma, Manoj Kumar
AU - Lal Das, Manish
AU - Wagh, Santosh
AU - Balakrishnan, Anand
AU - Johnson, Benjamin M.
AU - Santone, Kenneth S.
AU - Thalody, George
AU - Denton, Rex
AU - Saminathan, Hariharan
AU - Holenarsipur, Vinay K.
AU - Kumar, Anoop
AU - Rao, Abhijith
AU - Putlur, Siva Prasad
AU - Sarvasiddhi, Sarat Kumar
AU - Shankar, Ganesh
AU - Louis, Justin V.
AU - Ramarao, Manjunath
AU - Conway, Charles M.
AU - Li, Yu Wen
AU - Pieschl, Rick
AU - Tian, Yuan
AU - Hong, Yang
AU - Bristow, Linda
AU - Albright, Charles F.
AU - Bronson, Joanne J.
AU - MacOr, John E.
AU - Dzierba, Carolyn D.
N1 - Publisher Copyright:
© 2022 American Chemical Society.
PY - 2022/3/24
Y1 - 2022/3/24
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85126602580&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85126602580&partnerID=8YFLogxK
U2 - 10.1021/acs.jmedchem.1c02132
DO - 10.1021/acs.jmedchem.1c02132
M3 - Article
C2 - 35261239
AN - SCOPUS:85126602580
SN - 0022-2623
VL - 65
SP - 4534
EP - 4564
JO - Journal of Medicinal Chemistry
JF - Journal of Medicinal Chemistry
IS - 6
ER -