title: Identification and optimization of indolo[2,3-c]quinoline inhibitors of IRAK4.
abstract: 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 clogP. 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.
authors.affiliation: Pfizer Global R&D, 445 Eastern Point Rd., Groton, CT 06340, USA. Electronic address: Nathan.tumey@pfizer.com.
authors.forename: L Nathan
authors.initials: LN
authors.lastname: Tumey
authors.affiliation: Pfizer Global R&D, 445 Eastern Point Rd., Groton, CT 06340, USA.
authors.forename: Diane H
authors.initials: DH
authors.lastname: Boschelli
authors.affiliation: Pfizer Global R&D, 445 Eastern Point Rd., Groton, CT 06340, USA.
authors.forename: Niala
authors.initials: N
authors.lastname: Bhagirath
authors.affiliation: Pfizer Global R&D, 445 Eastern Point Rd., Groton, CT 06340, USA.
authors.forename: Jaechul
authors.initials: J
authors.lastname: Shim
authors.affiliation: Pfizer Global R&D, 200 Cambridge Park Dr., Cambridge, MA 02140, USA.
authors.forename: Elizabeth A
authors.initials: EA
authors.lastname: Murphy
authors.affiliation: Pfizer Global R&D, 200 Cambridge Park Dr., Cambridge, MA 02140, USA.
authors.forename: Deborah
authors.initials: D
authors.lastname: Goodwin
authors.affiliation: Pfizer Global R&D, 87 Cambridgepark Dr., Cambridge, MA 02140, USA.
authors.forename: Eric M
authors.initials: EM
authors.lastname: Bennett
authors.affiliation: Pfizer Global R&D, 1 Burtt Rd., Andover, MA 01810, USA.
authors.forename: Mengmeng
authors.initials: M
authors.lastname: Wang
authors.affiliation: Pfizer Global R&D, 200 Cambridge Park Dr., Cambridge, MA 02140, USA.
authors.forename: Lih-Ling
authors.initials: LL
authors.lastname: Lin
authors.affiliation: Pfizer Global R&D, 445 Eastern Point Rd., Groton, CT 06340, USA.
authors.forename: Barry
authors.initials: B
authors.lastname: Press
authors.affiliation: Pfizer Global R&D, 200 Cambridge Park Dr., Cambridge, MA 02140, USA.
authors.forename: Marina
authors.initials: M
authors.lastname: Shen
authors.affiliation: Pfizer Global R&D, 445 Eastern Point Rd., Groton, CT 06340, USA.
authors.forename: Richard K
authors.initials: RK
authors.lastname: Frisbie
authors.affiliation: Pfizer Global R&D, 200 Cambridge Park Dr., Cambridge, MA 02140, USA.
authors.forename: Paul
authors.initials: P
authors.lastname: Morgan
authors.affiliation: Pfizer Global R&D, 200 Cambridge Park Dr., Cambridge, MA 02140, USA.
authors.forename: Shashi
authors.initials: S
authors.lastname: Mohan
authors.affiliation: Pfizer Global R&D, 200 Cambridge Park Dr., Cambridge, MA 02140, USA.
authors.forename: Julia
authors.initials: J
authors.lastname: Shin
authors.affiliation: Pfizer Global R&D, 200 Cambridge Park Dr., Cambridge, MA 02140, USA.
authors.forename: Vikram R
authors.initials: VR
authors.lastname: Rao
mesh_terms: D000818:Animals; D005260:Female; D006801:Humans; D007211:Indoles / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology*; D053592:Interleukin-1 Receptor-Associated Kinases / Q000037:antagonists & inhibitors* / Q000276:immunology; D008070:Lipopolysaccharides / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D008958:Models, Molecular; D047428:Protein Kinase Inhibitors / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology*; D011804:Quinolines / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D007211:Indoles; D008070:Lipopolysaccharides; D047428:Protein Kinase Inhibitors; D011804:Quinolines; D053592:Interleukin-1 Receptor-Associated Kinases
keywords: IRAK4; Indoloquinoline; Inflammation; Kinase inhibitor; TLR signaling