Discovery of 5-Amino-N-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide Inhibitors of IRAK4

Abstract

Interleukin-1 receptor associated kinase 4 (IRAK4) is an essential signal transducer downstream of the IL-1R and TLR superfamily, and selective inhibition of the kinase activity of the protein represents an attractive target for the treatment of inflammatory diseases. A series of 5-amino-N-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamides was developed via sequential modifications to the 5-position of the pyrazolopyrimidine ring and the 3-position of the pyrazole ring. Replacement of substituents responsible for poor permeability and improvement of physical properties guided by cLogD led to the identification of IRAK4 inhibitors with excellent potency, kinase selectivity, and pharmacokinetic properties suitable for oral dosing.

Selective interleukin-1 receptor–associated kinase 4 inhibitors for the treatment of autoimmune disorders and lymphoid malignancy

“… McElroy et al (2015) describe an amidopyrazole IRAK4 inhibitor with good solubility and modest protein binding, which exhibits paw size reduction in a mouse model of arthritis. However, a subsequent publication by the same group ( Lim et al, 2015 ) describes the difficulty in obtaining desired drug-like properties (selectivity, permeability, and cell potency) in this series of compounds. In contrast, our thienopyrimidine compounds described herein possess excellent selectivity and solubility, low protein binding, good permeability and cell potency, and in vivo activity in several autoimmune and tumor efficacy models.…”

Crystal structure of human IRAK1

“…Innate immune signaling has an essential role in inflammation, and the dysregulation of signaling components of this pathway is increasingly being recognized as an important factor in cancer initiation, progression, and metastasis, as well as in autoimmunity. However, among the four IRAKs, only the IRAK4 kinase domain structure has been determined, both alone and in complex with various inhibitors (10,(21)(22)(23)(24)(25)(26)(27)(28)(29)(30). No structural information is currently available for IRAK1.…”

Identification of Toll-like receptor signaling inhibitors based on selective activation of hierarchically acting signaling proteins

“…In contrast to the scaffolding function of IRAK4, which is essential for canonical signaling pathways such as NF-kB, the kinase function of IRAK4 appears to play a minor role in canonical TLR pathways, but rather controls a subset of TLR-induced genes in a monocyte-specific way, possibly through mRNA stabilization (44,(55)(56)(57)(58). Still, inhibition of IRAK4 kinase activity in monocytes results in strongly reduced cytokine production (55,57), and an increasing number of chemically diverse, selective kinase inhibitors have been developed, several of which demonstrated in vivo efficacy in proofof-principle models (59)(60)(61)(62)(63)(64)(65)(66)(67)(68). Although most IRAK4 inhibitors showed in vivo PK properties requiring further improvement, a very recently published compound, Pf-06650833, showed remarkable in vivo potency (2.4 nM IC 50 on R848-induced peripheral blood mononuclear cells) and selectivity and has been moved forward to clinical studies (69).…”