0410 Science Center Drive

San Diego, CA, United States

0410 Science Center Drive

San Diego, CA, United States
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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.


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.


Dong Q.,0410 Science Center Drive | Dong Q.,Shanghai Hengrui Pharmaceuticals Co | Dougan D.R.,0410 Science Center Drive | Gong X.,0410 Science Center Drive | And 8 more authors.
Bioorganic and Medicinal Chemistry Letters | Year: 2011

A novel 5-phenylamino-8-methylpyrido[2,3-d]pyrimidine-4,7(3H,8H)-dione series of MEK inhibitors has been developed using structure-based drug design. Lead optimization of this series led to the discovery of TAK-733. This was advanced to Phase I clinical studies for cancer treatment. © 2011 Published by Elsevier Ltd.


Bressi J.C.,0410 Science Center Drive | Jong R.d.,0410 Science Center Drive | Wu Y.,0410 Science Center Drive | Jennings A.J.,0410 Science Center Drive | And 8 more authors.
Bioorganic and Medicinal Chemistry Letters | Year: 2010

A series of N-hydroxy-3-[3-(1-substituted-1H-benzoimidazol-2-yl)-phenyl]-acrylamides (5a-5ab) and N-hydroxy-3-[3-(1,4,5-trisubstituted-1H-imidazol-2-yl)-phenyl]-acrylamides (12a-s) were designed, synthesized, and found to be nanomolar inhibitors of human histone deacetylases. Multiple compounds bearing an N1-piperidine demonstrate EC50s of 20-100 nM in human A549, HL60, and PC3 cells, in vitro and in vivo hyperacetylation of histones H3 and H4, and induction of p21waf. Compound 5x displays efficacy in human tumor xenograft models. © 2010 Elsevier Ltd. All rights reserved.


Bressi J.C.,0410 Science Center Drive | Jennings A.J.,0410 Science Center Drive | Skene R.,0410 Science Center Drive | Wu Y.,0410 Science Center Drive | And 6 more authors.
Bioorganic and Medicinal Chemistry Letters | Year: 2010

A series of N-(2-amino-5-substituted phenyl)benzamides (3-21) were designed, synthesized and evaluated for their inhibition of HDAC2 and their cytotoxicity in HCT116 cancer cells. Multiple compounds from this series demonstrated time-dependent binding kinetics that is rationalized using a co-complex crystal structure of HDAC2 and N-(4-aminobiphenyl-3-yl)benzamide (6). © 2010 Elsevier Ltd. All rights reserved.


Wallace M.B.,0410 Science Center Drive | Scorah N.,0410 Science Center Drive | Vu P.H.,0410 Science Center Drive | Brown J.W.,0410 Science Center Drive | And 2 more authors.
Tetrahedron Letters | Year: 2010

An efficient, versatile, and scalable route for the synthesis of 7-aza-α-carboline compounds is described. The tricyclic system has been prepared from modified pyrazinones using a key intramolecular [4+2] Diels-Alder transformation. © 2010 Elsevier Ltd. All rights reserved.


Wallace M.B.,0410 Science Center Drive | Adams M.E.,0410 Science Center Drive | Kanouni T.,0410 Science Center Drive | Mol C.D.,0410 Science Center Drive | And 6 more authors.
Bioorganic and Medicinal Chemistry Letters | Year: 2010

A novel series of pyrrole inhibitors of MEK kinase has been developed using structure-based drug design. Optimization of the series led to the identification of potent inhibitors with good pharmaceutical properties. © 2010 Elsevier Ltd. All rights reserved.


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.


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.


PubMed | 0410 Science Center Drive
Type: Journal Article | Journal: Bioorganic & medicinal chemistry letters | Year: 2010

A novel series of pyrrole inhibitors of MEK kinase has been developed using structure-based drug design. Optimization of the series led to the identification of potent inhibitors with good pharmaceutical properties.

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