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Showing posts with label PF-05387552. Show all posts
Showing posts with label PF-05387552. Show all posts

Monday 18 April 2016

PF-05387552

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CID 50992153.png

PF-05387552

IRAK4
CAS 1604034-71-0
C25 H27 N5 O2
11H-​Indolo[3,​2-​c]​quinoline-​9-​carbonitrile, 2-​methoxy-​3-​[3-​(4-​methyl-​1-​piperazinyl)​propoxy]​-
2-methoxy-3-[3-(4-methylpiperazin-1-yl)propoxy]-11H-indolo[3,2-c]quinoline-9-carbonitrile
Molecular Weight429.51
Molecular Formula:C25H27N5O2
Molecular Weight:429.51418 g/mol

Synthesis

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

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

 a Pfizer Global R&D, 445 Eastern Point Rd., Groton, CT 06340, USA
  • 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
Image for unlabelled figure
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 TurneyL. Nathan Tumey, Ph.D., Principal Research Scientist, Pfizer Global R&D
REFERENCES
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///////////TLR signaling, Indoloquinoline, IRAK4, Kinase inhibitor, Inflammation, PF-05387552, PF 05387552,  1604034-71-0

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