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PF-05387552

IRAK4

Synthesis

PAPER

Bioorganic & Medicinal Chemistry Letters (2014), 24(9), 2066-2072

Bioorganic & Medicinal Chemistry Letters

Volume 24, Issue 9, 1 May 2014, Pages 2066–2072

Identification and optimization of indolo[2,3-c]quinoline inhibitors of IRAK4

• L. Nathan Tumey^{a, ,} ,
• Diane H. Boschelli^a,
• Niala Bhagirath^a,
• Jaechul Shim^a,
• Elizabeth A. Murphy^b,
• Deborah Goodwin^b,
• Eric M. Bennett^c,
• Mengmeng Wang^d,
• Lih-Ling Lin^b,
• Barry Press^a,
• Marina Shen^b,
• Richard K. Frisbie^a,
• Paul Morgan^b,
• Shashi Mohan^b,
• Julia Shin^b,
• Vikram R. Rao^b

• ^b Pfizer Global R&D, 200 Cambridge Park Dr., Cambridge, MA 02140, USA
• ^c Pfizer Global R&D, 87 Cambridgepark Dr., Cambridge, MA 02140, USA
• ^d Pfizer Global R&D, 1 Burtt Rd., Andover, MA 01810, USA

http://www.sciencedirect.com/science/article/pii/S0960894X14002832?np=y

IRAK4 is responsible for initiating signaling from Toll-like receptors (TLRs) and members of the IL-1/18 receptor family. Kinase-inactive knock-ins and targeted deletions of IRAK4 in mice cause reductions in TLR induced pro-inflammatory cytokines and these mice are resistant to various models of arthritis.

Herein we report the identification and optimization of a series of potent IRAK4 inhibitors. Representative examples from this series showed excellent selectivity over a panel of kinases, including the kinases known to play a role in TLR-mediated signaling. The compounds exhibited low nM potency in LPS- and R848-induced cytokine assays indicating that they are blocking the TLR signaling pathway.

A key compound (26) from this series was profiled in more detail and found to have an excellent pharmaceutical profile as measured by predictive assays such as microsomal stability, TPSA, solubility, and c log P. However, this compound was found to afford poor exposure in mouse upon IP or IV administration. We found that removal of the ionizable solubilizing group (32) led to increased exposure, presumably due to increased permeability. Compounds 26 and 32, when dosed to plasma levels corresponding to ex vivo whole blood potency, were shown to inhibit LPS-induced TNFα in an in vivo murine model.

To our knowledge, this is the first published in vivo demonstration that inhibition of the IRAK4 pathway by a small molecule can recapitulate the phenotype of IRAK4 knockout mice.

L. Nathan Tumey, Ph.D., Principal Research Scientist, Pfizer Global R&D

REFERENCES

///////////TLR signaling, Indoloquinoline, IRAK4, Kinase inhibitor, Inflammation, PF-05387552, PF 05387552,  1604034-71-0

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