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Timothy A Stammers,
René Coulombe,
Jean Rancourt,
Bounkham Thavonekham,
Gulrez Fazal,
Sylvie Goulet,
Araz Jakalian,
Dominic Wernic,
Youla Tsantrizos,
Marc-André Poupart, Michael Bös,
Ginette McKercher,
Louise Thauvette,
George Kukolj,
Pierre L Beaulieu
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ABSTRACT: A novel series of non-nucleoside thumb pocket 2 HCV NS5B polymerase inhibitors were derived from a fragment-based approach using information from X-ray crystallographic analysis of NS5B-inhibitor complexes and iterative rounds of parallel synthesis. Structure-based drug design strategies led to the discovery of potent sub-micromolar inhibitors 11a-c and 12a-c from a weak-binding fragment-like structure 1 as a starting point.
Bioorganic & medicinal chemistry letters 03/2013; · 2.65 Impact Factor
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Pierre L Beaulieu, Michael Bös,
Michael G Cordingley,
Catherine Chabot,
Gulrez Fazal,
Michel Garneau,
James R Gillard,
Eric Jolicoeur,
Steven Laplante,
Ginette McKercher,
Martin Poirier,
Marc-André Poupart,
Youla S Tsantrizos,
Jianmin Duan,
George Kukolj
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ABSTRACT: Combinations of direct acting antivirals (DAAs) that have the potential to suppress emergence of resistant virus and that can be used in interferon-sparing regimens represent a preferred option for the treatment of chronic HCV infection. We have discovered allosteric (thumb pocket 1) non-nucleoside inhibitors of HCV NS5B polymerase that inhibit replication in replicon systems. Herein, we report the late-stage optimization of indole-based inhibitors, which began with the identification of a metabolic liability common to many previously reported inhibitors in this series. By use of parallel synthesis techniques, a sparse matrix of inhibitors was generated that provided a collection of inhibitors satisfying potency criteria and displaying improved in vitro ADME profiles. "Cassette" screening for oral absorption in rat provided a short list of potential development candidates. Further evaluation led to the discovery of the first thumb pocket 1 NS5B inhibitor (BILB 1941) that demonstrated antiviral activity in patients chronically infected with genotype 1 HCV.
Journal of Medicinal Chemistry 07/2012; 55(17):7650-66. · 4.80 Impact Factor
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Lee D Fader,
Richard Bethell,
Pierre Bonneau, Michael Bös,
Yves Bousquet,
Michael G Cordingley,
René Coulombe,
Patrick Deroy,
Anne-Marie Faucher,
Alexandre Gagnon, [......],
Jean-Eric Lacoste,
Serge Landry,
Christopher T Lemke,
Eric Malenfant,
Stephen Mason,
Sébastien Morin,
Jeff O'Meara,
Bruno Simoneau,
Steve Titolo,
Christiane Yoakim
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ABSTRACT: The discovery of a 1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione series of inhibitors of HIV-1 capsid assembly is described. Synthesis of analogs of the 1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione hit established structure-activity relationships. Replacement of the enamine functionality of the hit series with either an imidazole or a pyrazole ring led to compounds that inhibited both capsid assembly and reverse transcriptase. Optimization of the bicyclic benzodiazepine scaffold to include a 3-phenyl substituent led to lead compound 48, a pure capsid assembly inhibitor with improved antiviral activity.
Bioorganic & medicinal chemistry letters 10/2010; 21(1):398-404. · 2.65 Impact Factor
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Montse Llinàs-Brunet,
Murray D Bailey,
Nathalie Goudreau,
Punit K Bhardwaj,
Josée Bordeleau, Michael Bös,
Yves Bousquet,
Michael G Cordingley,
Jiamin Duan,
Pat Forgione,
Michel Garneau,
Elise Ghiro,
Vida Gorys,
Sylvie Goulet,
Ted Halmos,
Stephen H Kawai,
Julie Naud,
Marc-André Poupart,
Peter W White
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ABSTRACT: C-Terminal carboxylic acid containing inhibitors of the NS3 protease are reported. A novel series of linear tripeptide inhibitors that are very potent and selective against the NS3 protease are described. A substantial contribution to the potency of these linear inhibitors arises from the introduction of a C8 substituent on the B-ring of the quinoline moiety found on the P2 of these inhibitors. The introduction of a C8 methyl group results not only in a modest increase in the cell-based potency of these inhibitors but more importantly in a much better pharmacokinetic profile in rats as well. Exploration of C8-substitutions led to the identification of the bromo derivative as the best group at this position, resulting in a significant increase in the cell-based potency of this class of inhibitors. Structure-activity studies on the C8-bromo derivatives ultimately led to the discovery of clinical candidate 29 (BI 201335), a very potent and selective inhibitor of genotype1 NS3 protease with a promising PK profile in rats.
Journal of Medicinal Chemistry 09/2010; 53(17):6466-76. · 4.80 Impact Factor
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British Journal of Pharmacology 02/2009; 124(3):556 - 562. · 4.41 Impact Factor
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Torsten Hoffmann, Michael Bös,
Heinz Stadler,
Patrick Schnider,
Walter Hunkeler,
Thierry Godel,
Guido Galley,
Theresa M Ballard,
Guy A Higgins,
Sonia M Poli,
Andrew J Sleight
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ABSTRACT: The discovery of a novel, achiral pyridine class of potent and orally active neurokinin-1 (NK(1)) receptor antagonists is described. The evaluation of this class is briefly outlined, leading to the identification of netupitant 21 and befetupitant 29, two new proprietary chemical entities with high affinity and excellent CNS penetration.
Bioorganic & Medicinal Chemistry Letters 04/2006; 16(5):1362-5. · 2.55 Impact Factor
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Progress in Medicinal Chemistry 02/2006; 44:65-107.
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Jeff A O'Meara,
Christiane Yoakim,
Pierre R Bonneau, Michael Bös,
Michael G Cordingley,
Robert Déziel,
Louise Doyon,
Jianmin Duan,
Michel Garneau,
Ingrid Guse,
Serge Landry,
Eric Malenfant,
Julie Naud,
William W Ogilvie,
Bounkham Thavonekham,
Bruno Simoneau
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ABSTRACT: A series of novel 8-substituted dipyridodiazepinone-based inhibitors were investigated for their antiviral activity against wild type human immunodeficiency virus (HIV-1) and the clinically prevalent K103N/Y181C mutant virus. Our efforts have resulted in a series of benzoic acid analogues that are potent inhibitors of HIV-1 replication against a panel of HIV-1 strains resistant to non-nucleoside reverse transcriptase inhibitors (NNRTIs). Furthermore, the combination of good antiviral potency, a broad spectrum of activity, and an excellent pharmacokinetic profile provides strong justification for the further development of compound (7) as a potential treatment for wild type and NNRTI-resistant HIV-1 infection.
Journal of Medicinal Chemistry 09/2005; 48(17):5580-8. · 5.25 Impact Factor
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ABSTRACT: The application of molecular biological techniques has revealed the existence of gene products encoding several novel putative receptors for the neurotransmitter 5-hydroxytryptamine (5-HT). For most of these novel receptors, no prior pharmacological or functional data existed, and the present challenges to pharmacologists are to identify tools to study these gene products, to determine whether or not they function as endogenous receptors and to determine potential therapeutic uses of ligands for these receptors. Here, we review work detailing the cloning and characterisation of the 5-HT6 receptor, its distribution and evidence for functional responses mediated by naturally-occurring 5-HT6 receptors.
02/2005; 8(10):1217-1224.
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ABSTRACT: Based on O-methylasparvenone (1), a N-free 5HT2C antagonist with moderate affinity (pKi = 6.7), derivatives bearing dimethylamino (7), (dimethylamino)methyl (17, 18, 21, and 22), and aminomethyl substituents (26) in place of the benzylic OH group of 1 as well as pyrrolidine- (33) and piperidine-fused derivatives (29, 43, and 45) were synthesized. In contrast to the lead structure 1, these new ligands were active in vivo in the rat. The tricycles 33 and 45 display high affinities for the 5HT2C receptor (pKi = 8).
Helvetica Chimica Acta 10/2004; 81(3‐4):525 - 538. · 1.48 Impact Factor
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Pierre L Beaulieu, Michael Bös,
Yves Bousquet,
Patrick DeRoy,
Gulrez Fazal,
Jean Gauthier,
James Gillard,
Sylvie Goulet,
Ginette McKercher,
Marc-André Poupart,
Serge Valois,
George Kukolj
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ABSTRACT: Optimization of benzimidazole 5-carboxamide derivatives previously identified as specific inhibitors of the NS5B polymerase of the hepatitis C virus (HCV) has led to the discovery of potent analogues that inhibit the enzyme at low-nanomolar concentrations. Greater than 800-fold improvement in potency from the original lead structure was achieved through the combined effects of conformational rigidification, molecular size extension and the identification of previously unexploited interactions. Furthermore, these inhibitors retain specificity for HCV polymerase relative to other viral and mammalian RNA polymerases.
Bioorganic & Medicinal Chemistry Letters 03/2004; 14(4):967-71. · 2.55 Impact Factor
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Pierre L Beaulieu, Michael Bös,
Yves Bousquet,
Gulrez Fazal,
Jean Gauthier,
James Gillard,
Sylvie Goulet,
Steven LaPlante,
Marc-André Poupart,
Sylvain Lefebvre,
Ginette McKercher,
Charles Pellerin,
Volkhard Austel,
George Kukolj
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ABSTRACT: Benzimidazole 5-carboxamide derivatives from a combinatorial screening library were discovered as specific inhibitors of the NS5B polymerase of the hepatitis C virus (HCV). Initial hit-to-lead activities taking advantage of high-throughput parallel synthetic techniques, identified a 1,2-disubstituted benzimidazole 5-carboxylic acid scaffold as the minimum core for biological activity. Potent analogues in this series inhibit the polymerase at low micromolar concentrations and provide an attractive "drug-like" lead structure for further optimization and the development of potential HCV therapeutics.
Bioorganic & Medicinal Chemistry Letters 02/2004; 14(1):119-24. · 2.55 Impact Factor
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Daniel Lamarre,
Paul C Anderson,
Murray Bailey,
Pierre Beaulieu,
Gordon Bolger,
Pierre Bonneau, Michael Bös,
Dale R Cameron,
Mireille Cartier,
Michael G Cordingley, [......],
Jean Rancourt,
Roel E Sentjens,
Roger St George,
Bruno Simoneau,
Gerhard Steinmann,
Diane Thibeault,
Youla S Tsantrizos,
Steven M Weldon,
Chan-Loi Yong,
Montse Llinàs-Brunet
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ABSTRACT: Hepatitis C virus (HCV) infection is a serious cause of chronic liver disease worldwide with more than 170 million infected individuals at risk of developing significant morbidity and mortality. Current interferon-based therapies are suboptimal especially in patients infected with HCV genotype 1, and they are poorly tolerated, highlighting the unmet medical need for new therapeutics. The HCV-encoded NS3 protease is essential for viral replication and has long been considered an attractive target for therapeutic intervention in HCV-infected patients. Here we identify a class of specific and potent NS3 protease inhibitors and report the evaluation of BILN 2061, a small molecule inhibitor biologically available through oral ingestion and the first of its class in human trials. Administration of BILN 2061 to patients infected with HCV genotype 1 for 2 days resulted in an impressive reduction of HCV RNA plasma levels, and established proof-of-concept in humans for an HCV NS3 protease inhibitor. Our results further illustrate the potential of the viral-enzyme-targeted drug discovery approach for the development of new HCV therapeutics.
Nature 12/2003; 426(6963):186-9. · 36.28 Impact Factor
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ABSTRACT: A small series of aryl pyridyl sulfones has been prepared and investigated for its 5-HT(6) receptor binding properties. Thereof, pyrrolidinyl derivative 11 proved to be a very potent (pK(i) 9) and selective 5-HT(6) receptor antagonist. By means of in vivo microdialysis in the frontal cortex and a passive avoidance paradigm, where 11 reversed a scopolamine induced retention deficit, a functional correlation between 5-HT(6) receptors and cholinergic neurotransmission could be shown, supporting the therapeutic potential of 5-HT(6) receptors in the treatment of cognitive deficits.
Journal of Medicinal Chemistry 04/2003; 46(7):1273-6. · 5.25 Impact Factor
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ABSTRACT: A series of cis and trans configured 2,3,4,4a,5,10b-hexahydro-benz[h]isoquinoline-6(1H)-ones 2 were studied with respect to the binding affinity to the 5-HT2 subtype receptors. The influence of substituents in positions 7(R1), 8(R2) and 9(R3) on affinity and selectivity to 5-HT2A and 5-HT2c receptors and the preference of one diastereoisomer is discussed.
CHIMIA International Journal for Chemistry 10/2000; 54(11):669-671. · 1.21 Impact Factor
