Discovery of Potent Selective Nonzinc Binding Autotaxin Inhibitor BIO-32546.
Bin Ma, Lei Zhang, Lihong Sun, Zhili Xin, Gnanasambandam Kumaravel, Douglas Marcotte, Jayanth V Chodaparambil, Qin Wang, Angela Wehr, Jing Jing, Victor Sukbong Hong, Ti Wang, Carol Huang, Zhaohui Shao, Sha Mi
Author Information
Bin Ma: Medicinal Chemistry, Physical Biochemistry, Drug Metabolism & Pharmacokinetics, Discovery Bioassay, Neurology, Biogen Inc., 225 Binney St, Cambridge, Massachusetts 02142, United States. ORCID
Lei Zhang: Medicinal Chemistry, Physical Biochemistry, Drug Metabolism & Pharmacokinetics, Discovery Bioassay, Neurology, Biogen Inc., 225 Binney St, Cambridge, Massachusetts 02142, United States.
Lihong Sun: Medicinal Chemistry, Physical Biochemistry, Drug Metabolism & Pharmacokinetics, Discovery Bioassay, Neurology, Biogen Inc., 225 Binney St, Cambridge, Massachusetts 02142, United States.
Zhili Xin: Medicinal Chemistry, Physical Biochemistry, Drug Metabolism & Pharmacokinetics, Discovery Bioassay, Neurology, Biogen Inc., 225 Binney St, Cambridge, Massachusetts 02142, United States.
Gnanasambandam Kumaravel: Medicinal Chemistry, Physical Biochemistry, Drug Metabolism & Pharmacokinetics, Discovery Bioassay, Neurology, Biogen Inc., 225 Binney St, Cambridge, Massachusetts 02142, United States.
Douglas Marcotte: Medicinal Chemistry, Physical Biochemistry, Drug Metabolism & Pharmacokinetics, Discovery Bioassay, Neurology, Biogen Inc., 225 Binney St, Cambridge, Massachusetts 02142, United States.
Jayanth V Chodaparambil: Medicinal Chemistry, Physical Biochemistry, Drug Metabolism & Pharmacokinetics, Discovery Bioassay, Neurology, Biogen Inc., 225 Binney St, Cambridge, Massachusetts 02142, United States.
Qin Wang: Medicinal Chemistry, Physical Biochemistry, Drug Metabolism & Pharmacokinetics, Discovery Bioassay, Neurology, Biogen Inc., 225 Binney St, Cambridge, Massachusetts 02142, United States.
Angela Wehr: Medicinal Chemistry, Physical Biochemistry, Drug Metabolism & Pharmacokinetics, Discovery Bioassay, Neurology, Biogen Inc., 225 Binney St, Cambridge, Massachusetts 02142, United States.
Jing Jing: Medicinal Chemistry, Physical Biochemistry, Drug Metabolism & Pharmacokinetics, Discovery Bioassay, Neurology, Biogen Inc., 225 Binney St, Cambridge, Massachusetts 02142, United States.
Victor Sukbong Hong: Medicinal Chemistry, Physical Biochemistry, Drug Metabolism & Pharmacokinetics, Discovery Bioassay, Neurology, Biogen Inc., 225 Binney St, Cambridge, Massachusetts 02142, United States.
Ti Wang: Medicinal Chemistry, Physical Biochemistry, Drug Metabolism & Pharmacokinetics, Discovery Bioassay, Neurology, Biogen Inc., 225 Binney St, Cambridge, Massachusetts 02142, United States.
Carol Huang: Medicinal Chemistry, Physical Biochemistry, Drug Metabolism & Pharmacokinetics, Discovery Bioassay, Neurology, Biogen Inc., 225 Binney St, Cambridge, Massachusetts 02142, United States.
Zhaohui Shao: Medicinal Chemistry, Physical Biochemistry, Drug Metabolism & Pharmacokinetics, Discovery Bioassay, Neurology, Biogen Inc., 225 Binney St, Cambridge, Massachusetts 02142, United States.
Sha Mi: Medicinal Chemistry, Physical Biochemistry, Drug Metabolism & Pharmacokinetics, Discovery Bioassay, Neurology, Biogen Inc., 225 Binney St, Cambridge, Massachusetts 02142, United States.
Autotaxin (ATX) is a lysophospholipase D that is the main enzyme responsible for generating LPA in body fluids. Although ATX was isolated from a conditioned medium of melanoma cells, later it was discovered to play a critical role in vascular and neuronal development. ATX has also been implicated in primary brain tumor, fibrosis, and rheumatoid arthritis, as well as neurological diseases such as multiple sclerosis, Alzheimer's disease, and neuropathic pain. As ATX and LPA levels are increased upon neuronal injury, a selective ATX inhibitor could provide a new approach to treat neuropathic pain. Herein we describe the discovery of a novel series of nonzinc binding reversible ATX inhibitors, particularly a potent, selective, orally bioavailable, brain-penetrable tool compound BIO-32546, as well as its synthesis, X-ray cocrystal structure, pharmacokinetics, and in vivo efficacy.
