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Farmer L.J.,Vertex Pharmaceuticals | Farmer L.J.,Paraza Pharma. Inc. | Clark M.P.,Vertex Pharmaceuticals | Boyd M.J.,Vertex Pharmaceuticals | And 26 more authors.
ACS Medicinal Chemistry Letters | Year: 2017

In our efforts to develop novel small-molecule inhibitors for the treatment of influenza, we utilized molecular modeling and the X-ray crystal structure of the PB2 subunit of the influenza polymerase to optimize a series of acyclic β-amino acid inhibitors, highlighted by compound 4. Compound 4 showed good oral exposure in both rat and mouse. More importantly, it showed strong potency versus multiple influenza-A strains, including pandemic 2009 H1N1 and avian H5N1 strains and showed a strong efficacy profile in a mouse influenza model even when treatment was initiated 48 h after infection. Compound 4 offers good oral bioavailability with great potential for the treatment of both pandemic and seasonal influenza. © 2017 American Chemical Society.


Albrecht B.K.,Constellation Pharmaceuticals | Albrecht B.K.,Third Rock Ventures | Gehling V.S.,Constellation Pharmaceuticals | Hewitt M.C.,Constellation Pharmaceuticals | And 34 more authors.
Journal of Medicinal Chemistry | Year: 2016

In recent years, inhibition of the interaction between the bromodomain and extra-terminal domain (BET) family of chromatin adaptors and acetyl-lysine residues on chromatin has emerged as a promising approach to regulate the expression of important disease-relevant genes, including MYC, BCL-2, and NF-κB. Here we describe the identification and characterization of a potent and selective benzoisoxazoloazepine BET bromodomain inhibitor that attenuates BET-dependent gene expression in vivo, demonstrates antitumor efficacy in an MV-4-11 mouse xenograft model, and is currently undergoing human clinical trials for hematological malignancies (CPI-0610). © 2016 American Chemical Society.


Ahmad T.,University of Quebec at Montréal | Dansereau J.,University of Quebec at Montréal | Hebert M.,University of Quebec at Montréal | Grand-Maitre C.,Paraza Pharma Inc. | And 3 more authors.
Tetrahedron Letters | Year: 2016

A copper-catalyzed protocol for the chemoselective arylation of (1R,2R)-(−)-N-BOC-2-amino-1-(4-nitrophenyl)-1,3-propanediol using triarylbismuth reagents is reported. The reaction operates under simple and mild conditions, shows good functional group tolerance and allows the installation of ortho-, meta-, and para-substituted aryl groups in moderate to good yields. These arylated products are then transformed in two steps into their corresponding N-dichloroacetamide derivatives. This sequence provides an expedient access to 3-O-aryl chloramphenicol derivatives. © 2016 Elsevier Ltd


Deng Y.,Merck And Co. | Shipps Jr. G.W.,Merck And Co. | Zhao L.,Merck And Co. | Siddiqui M.A.,Merck And Co. | And 19 more authors.
Bioorganic and Medicinal Chemistry Letters | Year: 2014

A new class of quinoline-based kinase inhibitors has been discovered that both disrupt cyclin dependent 2 (CDK2) interaction with its cyclin A subunit and act as ATP competitive inhibitors. The key strategy for discovering this class of protein-protein disrupter compounds was to screen the monomer CDK2 in an affinity-selection/mass spectrometry-based technique and to perform secondary assays that identified compounds that bound only to the inactive CDK2 monomer and not the active CDK2/cyclin A heterodimer. Through a series of chemical modifications the affinity (Kd) of the original hit improved from 1 to 0.005 μM. © 2013 Elsevier Ltd. All rights reserved.


Meng Z.,Merck And Co. | Sun B.,Merck And Co. | Reddy P.A.,Merck And Co. | Siddiqui M.A.,Merck And Co. | Siddiqui M.A.,Paraza Pharma Inc.
Tetrahedron Letters | Year: 2013

Acid-mediated cyclizations of SEM-protected heterocyclic anilines and adjacent hydroxyls or enol ethers during SEM deprotection are reported. Strategies to suppress these side reactions and their potential synthetic utilities are also described. © 2013 Elsevier Ltd. All rights reserved.


Ding H.,University of California at Los Angeles | Deroy P.L.,Paraza Pharma Inc. | Perreault C.,Paraza Pharma Inc. | Larivee A.,Paraza Pharma Inc. | And 4 more authors.
Angewandte Chemie - International Edition | Year: 2015

An electrochemical method to synthesize the core macrolactam of diazonamides is described. Large ring-forming dehydrogenation is initiated by anodic oxidation at a graphite surface. The reaction requires no tailoring of the substrate and occurs at ambient temperature in aqueous DMF in an undivided cell open to air. This unique chemistry has enabled a concise, scalable preparation of DZ-2384; a refined analog of diazonamide A slated for clinical development as a cancer therapeutic. © 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

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