Discovery of BIO-8169─A Highly Potent, Selective, and Brain-Penetrant IRAK4 Inhibitor for the Treatment of Neuroinflammation.

Autor:	Pfaffenbach M; Department of Medicinal Chemistry, Biogen Inc., 225 Binney Street, Cambridge, Massachusetts 02142, United States., Bolduc PN; Department of Medicinal Chemistry, Biogen Inc., 225 Binney Street, Cambridge, Massachusetts 02142, United States., Xin Z; Department of Medicinal Chemistry, Biogen Inc., 225 Binney Street, Cambridge, Massachusetts 02142, United States., Gao F; Department of Medicinal Chemistry, Biogen Inc., 225 Binney Street, Cambridge, Massachusetts 02142, United States., Evans R; Department of Medicinal Chemistry, Biogen Inc., 225 Binney Street, Cambridge, Massachusetts 02142, United States., Fang T; Department of Acute Neurology, Biogen Inc., 225 Binney Street, Cambridge, Massachusetts 02142, United States., Chodaparambil JV; Physical Biochemistry, Biogen Inc., 225 Binney Street, Cambridge, Massachusetts 02142, United States., Henry KL; Department of Acute Neurology, Biogen Inc., 225 Binney Street, Cambridge, Massachusetts 02142, United States., Li P; Drug Metabolism and Pharmacokinetics, Biogen Inc., 225 Binney Street, Cambridge, Massachusetts 02142, United States., Mathieu S; Pharmaceutical Operations & Technology, Biogen Inc., 225 Binney Street, Cambridge, Massachusetts 02142, United States., Metrick C; Physical Biochemistry, Biogen Inc., 225 Binney Street, Cambridge, Massachusetts 02142, United States., Vera Rebollar JA; Department of Multiple Sclerosis and Immunology, Biogen Inc., 225 Binney Street, Cambridge, Massachusetts 02142, United States., Gu RF; Chemical Biology and Proteomics, Biogen Inc., Cambridge, Massachusetts 02142, United States., Mccarl CA; Department of Multiple Sclerosis and Immunology, Biogen Inc., 225 Binney Street, Cambridge, Massachusetts 02142, United States., Silbereis J; Department of Multiple Sclerosis and Immunology, Biogen Inc., 225 Binney Street, Cambridge, Massachusetts 02142, United States., Peterson EA; Department of Medicinal Chemistry, Biogen Inc., 225 Binney Street, Cambridge, Massachusetts 02142, United States.
Jazyk:	angličtina
Zdroj:	Journal of medicinal chemistry [J Med Chem] 2024 May 23; Vol. 67 (10), pp. 8383-8395. Date of Electronic Publication: 2024 May 02.
DOI:	10.1021/acs.jmedchem.4c00560
Abstrakt:	Interleukin receptor associated kinase 4 (IRAK4) plays an important role in innate immune signaling through Toll-like and interleukin-1 receptors and represents an attractive target for the treatment of inflammatory diseases and cancer. We previously reported the development of a potent, selective, and brain-penetrant imidazopyrimidine series of IRAK4 inhibitors. However, lead molecule BIO-7488 ( 1 ) suffered from low solubility which led to variable PK, compound accumulation, and poor in vivo tolerability. Herein, we describe the discovery of a series of pyridone analogs with improved solubility which are highly potent, selective and demonstrate desirable PK profiles including good oral bioavailability and excellent brain penetration. BIO-8169 ( 2 ) reduced the in vivo production of pro-inflammatory cytokines, was well tolerated in safety studies in rodents and dog at margins well above the predicted efficacious exposure and showed promising results in a mouse model for multiple sclerosis.
Databáze:	MEDLINE
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