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
  • 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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