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Dive into the research topics where Eric Therrien is active.

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Featured researches published by Eric Therrien.


Tetrahedron | 2003

Synthesis of functionally diverse bicyclic sulfonamides as constrained proline analogues and application to the design of potential thrombin inhibitors

Helen Sailes; Eric Therrien

Bicyclic sulfonamides were synthesized from 4-alkenyl N-alkenylsulfonyl l-prolines using a ring-closure metathesis reaction. Three types of bicyclic sulfonamides varying in the size of the second ring (5,5; 5,6; 5,7) were synthesized. A sulfonamide counterpart of an indolizidinone 2-carboxylic acid was synthesized and evaluated for its activity against the enzyme thrombin.


Bioorganic & Medicinal Chemistry Letters | 2009

N-Benzyl-1-heteroaryl-3-(trifluoromethyl)-1H-pyrazole-5-carboxamides as inhibitors of co-activator associated arginine methyltransferase 1 (CARM1).

Martin Allan; Sukhdev Manku; Eric Therrien; Natalie Nguyen; Sylvia Styhler; Marie-France Robert; Anne-Christine Goulet; Andrea J. Petschner; Gabi Rahil; A. Robert MacLeod; Robert Deziel; Jeffrey M. Besterman; Hannah Nguyen; Amal Wahhab

A series of N-benzyl-1-heteroaryl-3-(trifluoromethyl)-1H-pyrazole-5-carboxamides targeting co-activator associated arginine methyltransferase 1 (CARM1) have been designed and synthesized. The potency of these inhibitors was influenced by the nature of the heteroaryl fragment with the thiophene analogues being superior to thiazole, pyridine, isoindoline and benzofuran based inhibitors.


Bioorganic & Medicinal Chemistry Letters | 2009

1,2-Diamines as inhibitors of co-activator associated arginine methyltransferase 1 (CARM1).

Eric Therrien; Guillaume Larouche; Sukhdev Manku; Martin Allan; Natalie Nguyen; Sylvia Styhler; Marie-France Robert; Anne-Christine Goulet; Jeffrey M. Besterman; Hannah Nguyen; Amal Wahhab

We have identified the N(1)-benzyl-N(2)-methylethane-1,2-diamine unit as a substitute for the (S)-alanine benzylamide moiety for the design of co-activator associated arginine methyltransferase 1 (CARM1) inhibitors. The potency of these inhibitors is in the same order of magnitude as their predecessors and their clearance, volume of distribution, and half lives were greatly improved.


Bioorganic & Medicinal Chemistry Letters | 2002

Targeting thrombin and factor VIIa: design, synthesis, and inhibitory activity of functionally relevant indolizidinones

Eric Therrien; Kenneth Granberg; Ingemar Nilsson

Guided by molecular modeling, docking experiments, and available X-ray crystal structure data on the serine protease Factor VIIa and thrombin, a series of indolizidinone derivatives was designed and synthesized having diverse functionality at the P1, P2, and P3 sites.


Journal of Chemical Information and Modeling | 2014

Docking ligands into flexible and solvated macromolecules. 6. Development and application to the docking of HDACs and other zinc metalloenzymes inhibitors.

Eric Therrien; James L. Gleason; Nicolas Moitessier

Metalloenzymes are ubiquitous proteins which feature one or more metal ions either directly involved in the enzymatic activity and/or structural properties (i.e., zinc fingers). Several members of this class take advantage of the Lewis acidic properties of zinc ions to carry out their various catalytic transformations including isomerization or amide cleavage. These enzymes have been validated as drug targets for a number of diseases including cancer; however, despite their pharmaceutical relevance and the availability of crystal structures, structure-based drug design methods have been poorly and indirectly parametrized for these classes of enzymes. More specifically, the metal coordination component and proton transfers of the process of drugs binding to metalloenzymes have been inadequately modeled by current docking programs, if at all. In addition, several known issues, such as coordination geometry, atomic charge variability, and a potential proton transfer from small molecules to a neighboring basic residue, have often been ignored. We report herein the development of specific functions and parameters to account for zinc-drug coordination focusing on the above-listed phenomena and their impact on docking to zinc metalloenzymes. These atom-type-dependent but atomic charge-independent functions implemented into Fitted 3.1 enable the simulation of drug binding to metalloenzymes, considering an acid-base reaction with a neighboring residue when necessary with good accuracy.


Journal of Medicinal Chemistry | 2012

Virtual screening and computational optimization for the discovery of covalent prolyl oligopeptidase inhibitors with activity in human cells.

Stéphane De Cesco; Sébastien Deslandes; Eric Therrien; David Levan; Mickaël Cueto; Ralf Schmidt; Louis-David Cantin; Anthony Mittermaier; Lucienne Juillerat-Jeanneret; Nicolas Moitessier

Our docking program, Fitted, implemented in our computational platform, Forecaster, has been modified to carry out automated virtual screening of covalent inhibitors. With this modified version of the program, virtual screening and further docking-based optimization of a selected hit led to the identification of potential covalent reversible inhibitors of prolyl oligopeptidase activity. After visual inspection, a virtual hit molecule together with four analogues were selected for synthesis and made in one-five chemical steps. Biological evaluations on recombinant POP and FAPα enzymes, cell extracts, and living cells demonstrated high potency and selectivity for POP over FAPα and DPPIV. Three compounds even exhibited high nanomolar inhibitory activities in intact living human cells and acceptable metabolic stability. This small set of molecules also demonstrated that covalent binding and/or geometrical constraints to the ligand/protein complex may lead to an increase in bioactivity.


Journal of Chemical Information and Modeling | 2012

Integrating medicinal chemistry, organic/combinatorial chemistry, and computational chemistry for the discovery of selective estrogen receptor modulators with Forecaster, a novel platform for drug discovery.

Eric Therrien; Pablo Englebienne; Andrew G. Arrowsmith; Rodrigo Mendoza-Sanchez; Christopher R. Corbeil; Nathanael Weill; Valérie Campagna-Slater; Nicolas Moitessier

As part of a large medicinal chemistry program, we wish to develop novel selective estrogen receptor modulators (SERMs) as potential breast cancer treatments using a combination of experimental and computational approaches. However, one of the remaining difficulties nowadays is to fully integrate computational (i.e., virtual, theoretical) and medicinal (i.e., experimental, intuitive) chemistry to take advantage of the full potential of both. For this purpose, we have developed a Web-based platform, Forecaster, and a number of programs (e.g., Prepare, React, Select) with the aim of combining computational chemistry and medicinal chemistry expertise to facilitate drug discovery and development and more specifically to integrate synthesis into computer-aided drug design. In our quest for potent SERMs, this platform was used to build virtual combinatorial libraries, filter and extract a highly diverse library from the NCI database, and dock them to the estrogen receptor (ER), with all of these steps being fully automated by computational chemists for use by medicinal chemists. As a result, virtual screening of a diverse library seeded with active compounds followed by a search for analogs yielded an enrichment factor of 129, with 98% of the seeded active compounds recovered, while the screening of a designed virtual combinatorial library including known actives yielded an area under the receiver operating characteristic (AU-ROC) of 0.78. The lead optimization proved less successful, further demonstrating the challenge to simulate structure activity relationship studies.


Bioorganic & Medicinal Chemistry Letters | 2009

Sulfamides as novel histone deacetylase inhibitors

Amal Wahhab; David Smil; Alain Ajamian; Martin Allan; Yves Andre Chantigny; Eric Therrien; Natalie Nguyen; Sukhdev Manku; Silvana Leit; Jubrail Rahil; Andrea J. Petschner; Aihua Lu; Alina Nicolescu; Sylvain Lefebvre; Samuel Montcalm; Marielle Fournel; Theresa P. Yan; Zuomei Li; Jeffrey M. Besterman; Robert Deziel

The sulfamide moiety has been utilized to design novel HDAC inhibitors. The potency and selectivity of these inhibitors were influenced both by the nature of the scaffold, and the capping group. Linear long-chain-based analogs were primarily HDAC6-selective, while analogs based on the lysine scaffold resulted in potent HDAC1 and HDAC6 inhibitors.


Bioorganic & Medicinal Chemistry Letters | 2008

Design, synthesis, and thrombin-inhibitory activity of pyridin-2-ones as P2/P3 core motifs.

Daniel Simard; Malken Bayrakdarian; Eric Therrien; Ingemar Nilsson; Ola Fjellström

Guided by available X-ray crystal structure data on the serine protease thrombin, a series of pyridin-2-one derivatives were designed and synthesized having diverse functionality at the P(1) and P(3) sites. Potent in vitro activity against thrombin, with excellent selectivity over trypsin was found for selected analogues.


Tetrahedron Letters | 2002

Peptide coupling of unprotected amino acids through in situ p-nitrophenyl ester formation

Paul Gagnon; Xicai Huang; Eric Therrien; Jeffrey W. Keillor

Abstract Several series of dipeptides and tripeptides were prepared via an activation–coupling method involving the in situ formation of a p -nitrophenyl ester of an ( N -protected) amino acid, followed by coupling with an unprotected amino acid in partially aqueous solutions. The resulting peptide is easily isolated by precipitation. In general, the yields obtained are good to excellent and racemization is minimal. This method is particularly advantageous with respect to its simplicity and lack of obligatory side chain protection/deprotection steps.

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