DR ANTHONY MELVIN CRASTO,WorldDrugTracker, helping millions, A 90 % paralysed man in action for you, I am suffering from transverse mylitis and bound to a wheel chair, With death on the horizon, this will not stop me, Only God and death can..........
DR ANTHONY MELVIN CRASTO Ph.D ( ICT, Mumbai), INDIA, worlddrugtracker, 29Yrs Exp. in the feld of Organic Chemistry,Working for GLENMARK PHARMA at Navi Mumbai, INDIA. Serving chemists around the world. Helping them with websites on Chemistry.8 Million hits on google, world acclamation from industry, academia, drug authorities for websites, blogs and educational contribution
n, सुकून उतना ही देना प्रभू, जितने से जिंदगी चल जाये।औकात बस इतनी देना,कि औरों का भला हो जाये।...........P.S. : The views expressed are my personal and in no-way suggest the views of the professional body or the company that I represent.
Showing posts with label PF-05388169. Show all posts
Showing posts with label PF-05388169. Show all posts

Tuesday, 5 July 2016


CAS 1604034-78-7,  MF C22 H21 N3 O4
MW 391.42
11H-​Indolo[3,​2-​c]​quinoline-​9-​carbonitrile, 2-​methoxy-​3-​[2-​(2-​methoxyethoxy)​ethoxy]​-
IRAK4 inhibitor
Rheumatoid arthritis;


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
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.


//////////PF-05388169, TLR signaling, Indoloquinoline, IRAK4, Kinase inhibitor, Inflammation, PRECLINICAL, 1604034-78-7