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

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

  • J Med Chem. 2024 May 23;67(10):8383-8395. doi: 10.1021/acs.jmedchem.4c00560.
Magnus Pfaffenbach 1,  Philippe N Bolduc 1,  Zhili Xin 1,  Fang Gao 1,  Ryan Evans 1,  Terry Fang 2,  Jayanth V Chodaparambil 3,  Kate L Henry 2,  Pei Li 4,  Steven Mathieu 5,  Claire Metrick 3,  Jorge A Vera Rebollar 6,  Rong-Fang Gu 7,  Christie-Ann Mccarl 6,  John Silbereis 6,  Emily A Peterson 1
Affiliations

Affiliations

  • 1 Department of Medicinal Chemistry, Biogen Inc., 225 Binney Street, Cambridge, Massachusetts 02142, United States.
  • 2 Department of Acute Neurology, Biogen Inc., 225 Binney Street, Cambridge, Massachusetts 02142, United States.
  • 3 Physical Biochemistry, Biogen Inc., 225 Binney Street, Cambridge, Massachusetts 02142, United States.
  • 4 Drug Metabolism and Pharmacokinetics, Biogen Inc., 225 Binney Street, Cambridge, Massachusetts 02142, United States.
  • 5 Pharmaceutical Operations & Technology, Biogen Inc., 225 Binney Street, Cambridge, Massachusetts 02142, United States.
  • 6 Department of Multiple Sclerosis and Immunology, Biogen Inc., 225 Binney Street, Cambridge, Massachusetts 02142, United States.
  • 7 Chemical Biology and Proteomics, Biogen Inc., Cambridge, Massachusetts 02142, United States.
PMID: 38695469 DOI: 10.1021/acs.jmedchem.4c00560
Abstract

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.

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