The Discovery of 7-Isopropoxy-2-(1-methyl-2-oxabicyclo[2.1.1]hexan-4-yl)- N-(6-methylpyrazolo[1,5- a]pyrimidin-3-yl)imidazo[1,2- a]pyrimidine-6-carboxamide (BIO-7488), a Potent, Selective, and CNS-Penetrant IRAK4 Inhibitor for the Treatment of Ischemic Stroke

Ryan Evans; Philippe N Bolduc; Magnus Pfaffenbach; Fang Gao; Tricia May-Dracka; Terry Fang; Brian T Hopkins; Jayanth V Chodaparambil; Kate L Henry; Pei Li; Claire Metrick; Ashley Nelson; Patrick Trapa; Ankur Thomas; Linda Burkly; Emily A Peterson

doi:10.1021/acs.jmedchem.3c02226

The Discovery of 7-Isopropoxy-2-(1-methyl-2-oxabicyclo[2.1.1]hexan-4-yl)- N-(6-methylpyrazolo[1,5- a]pyrimidin-3-yl)imidazo[1,2- a]pyrimidine-6-carboxamide (BIO-7488), a Potent, Selective, and CNS-Penetrant IRAK4 Inhibitor for the Treatment of Ischemic Stroke

J Med Chem. 2024 Mar 28;67(6):4676-4690. doi: 10.1021/acs.jmedchem.3c02226. Epub 2024 Mar 11.

Authors

Affiliations

¹ Department of Medicinal Chemistry, Biogen, 225 Binney Street, Cambridge, Massachusetts 02142, United States.
² Department of Acute Neurology, Biogen, 225 Binney Street, Cambridge, Massachusetts 02142, United States.
³ Physical Biochemistry, Biogen, 225 Binney Street, Cambridge, Massachusetts 02142, United States.
⁴ Drug Metabolism and Pharmacokinetics, Biogen, 225 Binney Street, Cambridge, Massachusetts 02142, United States.

PMID: 38467640
DOI: 10.1021/acs.jmedchem.3c02226

Abstract

Interleukin receptor-associated kinase 4 (IRAK4) is a key node of signaling within the innate immune system that regulates the production of inflammatory cytokines and chemokines. The presence of damage-associated molecular patterns (DAMPs) after tissue damage such as stroke or traumatic brain injury (TBI) initiates signaling through the IRAK4 pathway that can lead to a feed-forward inflammatory loop that can ultimately hinder patient recovery. Herein, we describe the first potent, selective, and CNS-penetrant IRAK4 inhibitors for the treatment of neuroinflammation. Lead compounds from the series were evaluated in CNS PK/PD models of inflammation, as well as a mouse model of ischemic stroke. The SAR optimization detailed within culminates in the discovery of BIO-7488, a highly selective and potent IRAK4 inhibitor that is CNS penetrant and has excellent ADME properties.

MeSH terms

Animals
Cytokines
Humans
Interleukin-1 Receptor-Associated Kinases*
Ischemic Stroke*
Mice
Pyrimidines / pharmacology
Pyrimidines / therapeutic use
Signal Transduction

Substances

Interleukin-1 Receptor-Associated Kinases
Cytokines
Pyrimidines
IRAK4 protein, human