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Dive into the research topics where W. Cameron Black is active.

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Featured researches published by W. Cameron Black.


Bioorganic & Medicinal Chemistry Letters | 2008

The discovery of odanacatib (MK-0822), a selective inhibitor of cathepsin K.

Jacques Yves Gauthier; Nathalie Chauret; Wanda Cromlish; Sylvie Desmarais; Le T. Duong; Jean-Pierre Falgueyret; Donald B. Kimmel; Sonia Lamontagne; Serge Leger; Tammy LeRiche; Chun Sing Li; Frédéric Massé; Daniel J. McKay; Deborah A. Nicoll-Griffith; Renata Oballa; James T. Palmer; M. David Percival; Denis Riendeau; Joel Robichaud; Gideon A. Rodan; Sevgi B. Rodan; Carmai Seto; Michel Therien; Vouy-Linh Truong; Michael C. Venuti; Gregg Wesolowski; Robert N. Young; Robert Zamboni; W. Cameron Black

Odanacatib is a potent, selective, and neutral cathepsin K inhibitor which was developed to address the metabolic liabilities of the Cat K inhibitor L-873724. Substituting P1 and modifying the P2 side chain led to a metabolically robust inhibitor with a long half-life in preclinical species. Odanacatib was more selective in whole cell assays than the published Cat K inhibitors balicatib and relacatib. Evaluation in dermal fibroblast culture showed minimal intracellular collagen accumulation relative to less selective Cat K inhibitors.


Journal of Bone and Mineral Research | 2011

Cathepsin K inhibitors prevent bone loss in estrogen‐deficient rabbits

Brenda Pennypacker; Le T. Duong; T. Cusick; Patricia Masarachia; Michael A. Gentile; Jacques-Yves Gauthier; W. Cameron Black; Boyd B. Scott; Rana Samadfam; Susan Y. Smith; Donald B. Kimmel

Two cathepsin K inhibitors (CatKIs) were compared with alendronate (ALN) for their effects on bone resorption and formation in ovariectomized (OVX) rabbits. The OVX model was validated by demonstrating significant loss (9.8% to 12.8%) in lumbar vertebral bone mineral density (LV BMD) in rabbits at 13‐weeks after surgery, which was prevented by estrogen or ALN. A potent CatKI, L‐006235 (L‐235), dosed at 10 mg/kg per day for 27 weeks, significantly decreased LV BMD loss (p < .01) versus OVX‐vehicle control. ALN reduced spine cancellous mineralizing surface by 70%, whereas L‐235 had no effect. Similarly, endocortical bone‐formation rate and the number of double‐labeled Haversian canals in the femoral diaphysis were not affected by L‐235. To confirm the sparing effects of CatKI on bone formation, odanacatib (ODN) was dosed in food to achieve steady‐state exposures of 4 or 9 µM/day in OVX rabbits for 27 weeks. ODN at both doses prevented LV BMD loss (p < .05 and p < .001, respectively) versus OVX‐vehicle control to levels comparable with sham or ALN. ODN also dose‐dependently increased BMD at the proximal femur, femoral neck, and trochanter. Similar to L‐235, ODN did not reduce bone formation at any bone sites studied. The positive and highly correlative relationship of peak load to bone mineral content in the central femur and spine suggested that ODN treatment preserved normal biomechanical properties of relevant skeletal sites. Although CatKIs had similar efficacy to ALN in preventing bone loss in adult OVX rabbits, this novel class of antiresorptives differs from ALN by sparing bone formation, potentially via uncoupling bone formation from resorption.


Bioorganic & Medicinal Chemistry Letters | 2005

Trifluoroethylamines as amide isosteres in inhibitors of cathepsin K

W. Cameron Black; Christopher I. Bayly; Dana E. Davis; Sylvie Desmarais; Jean-Pierre Falgueyret; Serge Leger; Chun Sing Li; Frédéric Massé; Daniel J. McKay; James T. Palmer; M. David Percival; Joel Robichaud; Nancy N. Tsou; Robert Zamboni

The P2-P3 amide of dipeptide cathepsin K inhibitors can be replaced by the metabolically stable trifluoroethylamine group. The non-basic nature of the nitrogen allows the important hydrogen bond to Gly66 to be made. The resulting compounds are 10- to 20-fold more potent than the corresponding amide derivatives. Compound 8 is a 5 pM inhibitor of human cathepsin K with >10,000-fold selectivity over other cathepsins.


Journal of Medicinal Chemistry | 2011

Development of a Liver-Targeted Stearoyl-CoA Desaturase (SCD) Inhibitor (MK-8245) to Establish a Therapeutic Window for the Treatment of Diabetes and Dyslipidemia

Renata Oballa; Liette Belair; W. Cameron Black; Kelly Bleasby; Chi-Chung Chan; Carole Desroches; Xiaobing Du; Robert Gordon; Jocelyne Guay; Sébastien Guiral; Michael J. Hafey; Emelie Hamelin; Zheng Huang; Brian Kennedy; Nicolas Lachance; Chun Sing Li; Joseph A. Mancini; Denis Normandin; Alessandro Pocai; David Powell; Yeeman K. Ramtohul; Kathryn Skorey; Dan Sørensen; Wayne Sturkenboom; Angela Styhler; Deena Waddleton; Hao Wang; Simon Wong; Lijing Xu; Lei Zhang

The potential use of SCD inhibitors for the chronic treatment of diabetes and dyslipidemia has been limited by preclinical adverse events associated with inhibition of SCD in skin and eye tissues. To establish a therapeutic window, we embarked on designing liver-targeted SCD inhibitors by utilizing molecular recognition by liver-specific organic anion transporting polypeptides (OATPs). In doing so, we set out to target the SCD inhibitor to the organ believed to be responsible for the therapeutic efficacy (liver) while minimizing its exposure in the tissues associated with mechanism-based SCD depletion of essential lubricating lipids (skin and eye). These efforts led to the discovery of MK-8245 (7), a potent, liver-targeted SCD inhibitor with preclinical antidiabetic and antidyslipidemic efficacy with a significantly improved therapeutic window.


Bioorganic & Medicinal Chemistry Letters | 1999

Structure-based design of COX-2 selectivity into flurbiprofen.

Christopher I. Bayly; W. Cameron Black; Serge Leger; Nathalie Ouimet; Marc Ouellet; M. David Percival

Comparative computer modeling of the X-ray crystal structures of cyclooxygenase isoforms COX-1 and COX-2 has led to the design of COX-2 selectivity into the nonselective inhibitor flurbiprofen. The COX-2 modeling was based on a postulated binding mode for flurbiprofen and took advantage of a small alcove in the COX-2 active site created by different positions of the Leu384 sidechain between COX-1 and COX-2. The design hypothesis was tested by synthesis and biological assay of a series of flurbiprofen analogs, culminating in the discovery of several inhibitors having up to 78-fold selectivity for COX-2 over COX-1.


ChemBioChem | 2006

The Consequences of Lysosomotropism on the Design of Selective Cathepsin K Inhibitors

W. Cameron Black; M. David Percival

Many drug candidates contain a basic functional group that results in lysosomotropism—the accumulation of drug in the acidic lysosomes of a cell. When evaluating inhibitors of lysosomal enzymes, such as the cathepsins, this physical property can have a dramatic impact on the functional selectivity of the test compounds. A basic P3 substituent in cathepsin K inhibitors provides a means of achieving potent and selective enzyme inhibition. To evaluate the whole‐cell selectivity of the basic cathepsin K inhibitor L‐006235, we identified the irreversible pan‐selective cathepsin probe BIL‐DMK and used it to design whole‐cell enzyme‐occupancy assays. These cell‐based assays showed a dramatic reduction in selectivity against cathepsins B, L, and S relative to the selectivities observed in enzyme assays. Two‐photon confocal fluorescence microscopy showed punctated subcellular localization of L‐006235, which colocalized with BODIPY‐labelled Lysotracker, consistent with compound lysosomotropism. To address this potential problem, a series of potent cathepsin K inhibitors was developed by replacing the P2P3 amide bond with a metabolically stable trifluoroethylamine moiety. X‐ray crystallography has identified the binding of this functional group to active‐site residues in cathepsin K. This modification resulted in increased potency and selectivity that allowed the removal of the basic P3 substituent. The resulting nonbasic inhibitor L‐873724 is a 0.2 nM inhibitor of cathepsin K with cathepsin B, L, and S potencies that were not shifted between purified enzyme and whole‐cell assays; thus indicating that this compound is not lysosomotropic. L‐873724 exhibits excellent pharmacokinetics and is orally active in a monkey model of osteoporosis at 3 mg kg−1 q.d.


Bioorganic & Medicinal Chemistry Letters | 1996

Synthesis and biological evaluation of 2,3-diarylthiophenes as selective cox-2 inhibitors. part II: Replacing the heterocycle

Jacques Yves Gauthier; Yves Leblanc; W. Cameron Black; Chi-Chung Chan; Wanda Cromlish; Robert Gordon; Brian P. Kennedey; Cheuk K. Lau; Serge Leger; Zhaoyin Wang; Diane Ethier; Jocelyne Guay; Joseph A. Mancini; Denis Riendeau; Philip Tagari; Philip J. Vickers; Elizabeth Wong; Lijing Xu; Peptiboon Prasit

Abstract The thiophene ring of DuP 697 was replaced by a variety of heterocycles and the products were tested for their ability to inhibit human Cox-2 and Cox-1, the isozymes of cyclooxygenase.


Bioorganic & Medicinal Chemistry Letters | 2010

Synthesis and biological activity of a potent and orally bioavailable SCD inhibitor (MF-438)

Serge Leger; W. Cameron Black; Denis Deschenes; Sarah J. Dolman; Jean-Pierre Falgueyret; Marc Gagnon; Sébastien Guiral; Zheng Huang; Jocelyne Guay; Yves Leblanc; Chun-Sing Li; Frédéric Massé; Renata Oballa; Lei Zhang

A series of stearoyl-CoA desaturase 1 (SCD1) inhibitors were developed. Investigations of enzyme potency and metabolism led to the identification of the thiadiazole-pyridazine derivative MF-438 as a potent SCD1 inhibitor. MF-438 exhibits good pharmacokinetics and metabolic stability, thereby serving as a valuable tool for further understanding the role of SCD inhibition in biological and pharmacological models of diseases related to metabolic disorders.


Antimicrobial Agents and Chemotherapy | 2014

Reversible Cysteine Protease Inhibitors Show Promise for a Chagas Disease Cure

Momar Ndao; Christian Beaulieu; W. Cameron Black; Elise Isabel; Fabio Vasquez-Camargo; Milli Nath-Chowdhury; Frédéric Massé; Christophe Mellon; Nathalie Méthot; Deborah A. Nicoll-Griffith

ABSTRACT The cysteine protease cruzipain is essential for the viability, infectivity, and virulence of Trypanosoma cruzi, the causative agent of Chagas disease. Thus, inhibitors of cruzipain are considered promising anti-T. cruzi chemotherapeutic agents. Reversible cruzipain inhibitors containing a nitrile “warhead” were prepared and demonstrated 50% inhibitory concentrations (IC50s) as potent as 1 nM in baculovirus-generated cruzipain enzyme assays. In epimastigote and intracellular amastigote in vitro assays, the most potent compounds demonstrated antiparasitic behavior in the 5 to 10 μM IC50 range; however, trypomastigote production from the amastigote form was ∼90 to 95% inhibited at 2 μM. Two key compounds, Cz007 and Cz008, with IC50s of 1.1 and 1.8 nM, respectively, against the recombinant enzyme were tested in a murine model of acute T. cruzi infection, with oral dosing in chow for 28 days at doses from 3 to 50 mg/kg of body weight. At 3 mg/kg of Cz007 and 3 mg/kg of Cz008, the blood parasitemia areas under the concentration-time curves were 16% and 25% of the untreated group, respectively. At sacrifice, 24 days after immunosuppression with cyclophosphamide, parasite presence in blood, heart, and esophagus was evaluated. Based on negative quantitative PCR results in all three tissues, cure rates in surviving animals were 90% for Cz007 at 3 mg/kg, 78% for Cz008 at 3 mg/kg, and 71% for benznidazole, the control compound, at 50 mg/kg.


Drug Metabolism and Disposition | 2011

Pharmacokinetics and Metabolism in Rats, Dogs, and Monkeys of the Cathepsin K Inhibitor Odanacatib: Demethylation of a Methylsulfonyl Moiety as a Major Metabolic Pathway

Kelem Kassahun; W. Cameron Black; Deborah A. Nicoll-Griffith; Ian McIntosh; Nathalie Chauret; Stephen Day; Elizabeth Rosenberg; Kenneth A. Koeplinger

Odanacatib is a potent cathespin K inhibitor that is being developed as a novel therapy for osteoporosis. The disposition and metabolism of odanacatib were evaluated in rats, dogs, and rhesus monkeys after intravenous and oral administration of [14C]odanacatib. Odanacatib was characterized by low systemic clearance in all species and by a long plasma half-life in monkeys (18 h) and dogs (64 h). The oral bioavailability was dependent on the vehicle used and ranged from 18% (monkey) to ∼100% (dog) at doses of 1 to 5 mg/kg, using nonaqueous vehicles. After intravenous and oral administration to intact rats and monkeys >90% of the dose was recovered, mainly in the feces. Studies in bile duct-cannulated animals indicated that biliary secretion was the major mode of elimination of radioactivity; odanacatib also underwent some intestinal secretion. In monkeys, odanacatib was almost completely eliminated by metabolism; metabolism also played a major role in the clearance of odanacatib in rats and dogs. The major metabolic pathways were methyl hydroxylation (formation of M8 and its derivatives), methyl sulfone demethylation (formation of M4 and its derivative M5), and glutathione conjugation (formation of the cyclized cysteinylglycine adduct M6 after addition of glutathione to the nitrile group of odanacatib). The major metabolites in rats [M4 (parent-14 Da) and M5 (oxygenated derivative of M4)] were determined to arise from a novel pathway that involved oxidative demethylation of the methylsulfonyl moiety of odanacatib. Overall, odanacatib displayed species-dependent metabolism, which explains, at least in part, the divergent plasma half-life observed.

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