Discovery of Potent Selective Nonzinc Binding Autotaxin Inhibitor BIO-32546.

Autor:	Ma B; Medicinal Chemistry, Physical Biochemistry, Drug Metabolism & Pharmacokinetics, Discovery Bioassay, Neurology, Biogen Inc., 225 Binney St, Cambridge, Massachusetts 02142, United States., Zhang L; Medicinal Chemistry, Physical Biochemistry, Drug Metabolism & Pharmacokinetics, Discovery Bioassay, Neurology, Biogen Inc., 225 Binney St, Cambridge, Massachusetts 02142, United States., Sun L; Medicinal Chemistry, Physical Biochemistry, Drug Metabolism & Pharmacokinetics, Discovery Bioassay, Neurology, Biogen Inc., 225 Binney St, Cambridge, Massachusetts 02142, United States., Xin Z; Medicinal Chemistry, Physical Biochemistry, Drug Metabolism & Pharmacokinetics, Discovery Bioassay, Neurology, Biogen Inc., 225 Binney St, Cambridge, Massachusetts 02142, United States., Kumaravel G; Medicinal Chemistry, Physical Biochemistry, Drug Metabolism & Pharmacokinetics, Discovery Bioassay, Neurology, Biogen Inc., 225 Binney St, Cambridge, Massachusetts 02142, United States., Marcotte D; Medicinal Chemistry, Physical Biochemistry, Drug Metabolism & Pharmacokinetics, Discovery Bioassay, Neurology, Biogen Inc., 225 Binney St, Cambridge, Massachusetts 02142, United States., Chodaparambil JV; Medicinal Chemistry, Physical Biochemistry, Drug Metabolism & Pharmacokinetics, Discovery Bioassay, Neurology, Biogen Inc., 225 Binney St, Cambridge, Massachusetts 02142, United States., Wang Q; Medicinal Chemistry, Physical Biochemistry, Drug Metabolism & Pharmacokinetics, Discovery Bioassay, Neurology, Biogen Inc., 225 Binney St, Cambridge, Massachusetts 02142, United States., Wehr A; Medicinal Chemistry, Physical Biochemistry, Drug Metabolism & Pharmacokinetics, Discovery Bioassay, Neurology, Biogen Inc., 225 Binney St, Cambridge, Massachusetts 02142, United States., Jing J; Medicinal Chemistry, Physical Biochemistry, Drug Metabolism & Pharmacokinetics, Discovery Bioassay, Neurology, Biogen Inc., 225 Binney St, Cambridge, Massachusetts 02142, United States., Hong VS; Medicinal Chemistry, Physical Biochemistry, Drug Metabolism & Pharmacokinetics, Discovery Bioassay, Neurology, Biogen Inc., 225 Binney St, Cambridge, Massachusetts 02142, United States., Wang T; Medicinal Chemistry, Physical Biochemistry, Drug Metabolism & Pharmacokinetics, Discovery Bioassay, Neurology, Biogen Inc., 225 Binney St, Cambridge, Massachusetts 02142, United States., Huang C; Medicinal Chemistry, Physical Biochemistry, Drug Metabolism & Pharmacokinetics, Discovery Bioassay, Neurology, Biogen Inc., 225 Binney St, Cambridge, Massachusetts 02142, United States., Shao Z; Medicinal Chemistry, Physical Biochemistry, Drug Metabolism & Pharmacokinetics, Discovery Bioassay, Neurology, Biogen Inc., 225 Binney St, Cambridge, Massachusetts 02142, United States., Mi S; Medicinal Chemistry, Physical Biochemistry, Drug Metabolism & Pharmacokinetics, Discovery Bioassay, Neurology, Biogen Inc., 225 Binney St, Cambridge, Massachusetts 02142, United States.
Jazyk:	angličtina
Zdroj:	ACS medicinal chemistry letters [ACS Med Chem Lett] 2021 Jun 14; Vol. 12 (7), pp. 1124-1129. Date of Electronic Publication: 2021 Jun 14 (Print Publication: 2021).
DOI:	10.1021/acsmedchemlett.1c00211
Abstrakt:	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. Competing Interests: The authors declare no competing financial interest. (© 2021 American Chemical Society.)
Databáze:	MEDLINE
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