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Duffy J.P.,Vertex Pharmaceuticals | Harrington E.M.,Novartis | Salituro F.G.,Agios Pharmaceuticals | Cochran J.E.,Vertex Pharmaceuticals | And 17 more authors.
ACS Medicinal Chemistry Letters | Year: 2011

The synthesis of novel, selective, orally active 2,5-disubstituted 6H-pyrimido[1,6-b]pyridazin-6-one p38α inhibitors is described. Application of structural information from enzyme-ligand complexes guided the selection of screening compounds, leading to the identification of a novel class of p38α inhibitors containing a previously unreported bicyclic heterocycle core. Advancing the SAR of this series led to the eventual discovery of 5-(2,6-dichlorophenyl)-2-(2,4-difluorophenylthio)-6H-pyrimido[1,6-b] pyridazin-6-one (VX-745). VX-745 displays excellent enzyme activity and selectivity, has a favorable pharmacokinetic profile, and demonstrates good in vivo activity in models of inflammation. © 2011 American Chemical Society. Source


Lardy M.A.,Anadys Pharmaceuticals Inc. | Lardy M.A.,0410 Science Center Drive | Lebrun L.,Anadys Pharmaceuticals Inc. | Lebrun L.,Celgene | And 5 more authors.
Journal of Chemical Information and Modeling | Year: 2012

In modern day drug discovery campaigns, computational chemists have to be concerned not only about improving the potency of molecules but also reducing any off-target ADMET activity. There are a plethora of antitargets that computational chemists may have to consider. Fortunately many antitargets have crystal structures deposited in the PDB. These structures are immediately useful to our Autocorrelator: an automated model generator that optimizes variables for building computational models. This paper describes the use of the Autocorrelator to construct high quality docking models for cytochrome P450 2C9 (CYP2C9) from two publicly available crystal structures. Both models result in strong correlation coefficients (R 2 > 0.66) between the predicted and experimental determined log(IC 50) values. Results from the two models overlap well with each other, converging on the same scoring function, deprotonated charge state, and predicted the binding orientation for our collection of molecules. © 2012 American Chemical Society. Source


Hu Y.,Pfizer | Cole D.,0410 Science Center Drive | Denny R.A.,Pfizer | Anderson D.R.,Pfizer | And 11 more authors.
Bioorganic and Medicinal Chemistry Letters | Year: 2011

Synthesis, modeling and structure-activity relationship of indazoles as inhibitors of Tpl2 kinase are described. From a high throughput screening effort, we identified an indazole hit compound 5 that has a single digit micromolar Tpl2 activity. Through SAR modifications at the C3 and C5 positions of the indazole, we discovered compound 31 with good potency in LANCE assay and cell-based p-Erk assay. © 2011 Elsevier Ltd. All rights reserved. Source


Ni Y.,Pfizer | Gopalsamy A.,Pfizer | Cole D.,0410 Science Center Drive | Hu Y.,Pfizer | And 8 more authors.
Bioorganic and Medicinal Chemistry Letters | Year: 2011

We report here the synthesis and SAR of a new series of thieno[3,2-d]pyrimidines as potent Tpl2 kinase inhibitors. The proposed binding mode suggests the potential flipped binding mode depending on the substitution. Biacore studies show evidence of binding of these molecules to the protein kinase. The kinome inhibition profile of these molecules suggests good selectivity. © 2011 Elsevier Ltd. All rights reserved. Source


Pennington L.D.,Amgen | Whittington D.A.,Amgen | Bartberger M.D.,Amgen | Jordan S.R.,Amgen | And 12 more authors.
Bioorganic and Medicinal Chemistry Letters | Year: 2013

We describe a systematic study of how macrocyclization in the P 1-P3 region of hydroxyethylamine-based inhibitors of β-site amyloid precursor protein (APP)-cleaving enzyme (BACE1) modulates in vitro activity. This study reveals that in a number of instances macrocyclization of bis-terminal dienes leads to improved potency toward BACE1 and selectivity against cathepsin D (CatD), as well as greater amyloid β-peptide (Aβ)-lowering activity in HEK293T cells stably expressing APPSW. However, for several closely related analogs the benefits of macrocyclization are attenuated by the effects of other structural features in different regions of the molecules. X-ray crystal structures of three of these novel macrocyclic inhibitors bound to BACE1 revealed their binding conformations and interactions with the enzyme. © 2013 Elsevier Ltd. All rights reserved. Source

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