A5091001053- Computational Drug Discovery Methods
- SARS-CoV-2 and COVID-19 Research
- Molecular spectroscopy and chirality
- Asymmetric Synthesis and Catalysis
- RNA and protein synthesis mechanisms
- Cancer Treatment and Pharmacology
- Chemical Synthesis and Analysis
- Coordination Chemistry and Organometallics
- Cytomegalovirus and herpesvirus research
- Peptidase Inhibition and Analysis
- Herpesvirus Infections and Treatments
- Oxidative Organic Chemistry Reactions
- RNA modifications and cancer
- Chemistry and Stereochemistry Studies
- Pharmacogenetics and Drug Metabolism
- Organic Chemistry Synthesis Methods
- Marine Sponges and Natural Products
- COVID-19 Clinical Research Studies
- Microbial Natural Products and Biosynthesis
- Synthesis and Biological Activity
- Synthesis and Biological Evaluation
- Galectins and Cancer Biology
- Synthesis and Reactivity of Sulfur-Containing Compounds
- Drug Transport and Resistance Mechanisms
- Synthesis and characterization of novel inorganic/organometallic compounds
University of Alberta
2019-2024
Pfizer (United States)
2006-2020
NAEJA-RGM Pharmaceuticals (Canada)
2012-2013
University of British Columbia
2002
W.E. Upjohn Institute for Employment Research
2000-2001
University of Calgary
1993-2000
The novel coronavirus disease COVID-19 that emerged in 2019 is caused by the virus SARS CoV-2 and named for its close genetic similarity to CoV-1 severe acute respiratory syndrome (SARS) 2002. Both genomes encode two overlapping large polyproteins, which are cleaved at specific sites a 3C-like cysteine protease (3CLpro) post-translational processing step critical replication. 3CLpro sequences viruses 100% identical catalytic domain carries out protein cleavage. A research effort focused on...
Despite a high current standard of care in antiretroviral therapy for HIV, multidrug-resistant strains continue to emerge, underscoring the need additional novel mechanism inhibitors that will offer expanded therapeutic options clinic. We report new class small molecule compounds directly target HIV-1 capsid (CA) via action. The exhibit potent antiviral activity against laboratory strains, clinical isolates, and HIV-2, inhibit both early late events viral replication cycle. present...
The main protease of SARS-CoV-2 (Mpro) is the most promising drug target against coronaviruses due to its essential role in virus replication. With newly emerging variants there a concern that mutations Mpro may alter structural and functional properties subsequently potency existing potential antivirals. We explored effect 31 belonging 5 (VOCs) on catalytic parameters substrate specificity, which revealed changes binding rate cleavage viral peptide. Crystal structures 11 mutants provided...
Gram-negative bacteria cause approximately 70% of the infections in intensive care units. A growing number bacterial isolates responsible for these are resistant to currently available antibiotics and many development. Most agents under development modifications existing drug classes, which only partially overcome resistance mechanisms. Therefore, new classes antibacterials with truly novel modes action needed circumvent We have previously identified a way inhibit an aminoacyl-tRNA...
Abstract Blockade of the programmed cell death 1 (PD-1)/programmed death-ligand (PD-L1) interaction has emerged as a powerful strategy in cancer immunotherapy. Recently, there have been enormous efforts to develop potent PD-1/PD-L1 inhibitors. In particular, Bristol-Myers Squibb (BMS) and Aurigene Discovery Technologies individually disclosed several promising inhibitors, whose detailed experimental data are not publicly disclosed. this work, we report rigorous systematic vitro...
Recurring coronavirus outbreaks, such as the current COVID-19 pandemic, establish a necessity to develop direct-acting antivirals that can be readily administered and are active against broad spectrum of coronaviruses. Described in this Article novel α-acyloxymethylketone warhead peptidomimetic compounds with six-membered lactam glutamine mimic P1. Compounds potent SARS-CoV-2 3CL protease vitro viral replication inhibition were identified low cytotoxicity good plasma glutathione stability....
We have used boron-based molecules to create novel, competitive, reversible inhibitors of phosphodiesterase 4 (PDE4). The co-crystal structure reveals a binding configuration which is unique compared classical catechol PDE4 inhibitors, with boron the activated water in bimetal center. These phenoxybenzoxaboroles can be optimized generate submicromolar potency enzyme inhibit TNF-α, IL-2, IFN-γ, IL-5 and IL-10 activities vitro show safety efficacy for topical treatment human psoriasis. They...
Tragically, the death toll from COVID-19 pandemic continues to rise, and with variants being observed around globe new therapeutics, particularly direct-acting antivirals that are easily administered, desperately needed. Studies targeting SARS-CoV-2 3CL protease, which is critical for viral replication, different peptidomimetics warheads an active area of research development potential drugs. To date, however, only a few publications have evaluated nitrile warhead as protease inhibitor,...
The antimitotic sponge tripeptide hemiasterlin (1) and a number of structural analogues have been synthesized evaluated in cell-based assays for both cytotoxic activity order to explore the SAR this promising anticancer drug lead. One synthetic analogue, SPA110 (8), showed more potent vitro cytotoxicty than natural product (1), consequently it has subjected thorough preclinical evaluation targeted clinical evaluation. details synthesis discussion how their biological activities vary with...
[equation--see text] The first enantioselective synthesis of the martinelline core (-)-3 is reported. from N-allyl-N-(benzyloxycarbonyl)-2-iodoaniline (12) proceeded in seven steps and 23% overall yield. In addition, preparation a carbocyclic model system described.
Flutamide, a widely used nonsteroidal antiandrogen drug for the treatment of prostate cancer, has been associated with rare incidences hepatotoxicity in patients. It is believed that bioactivation flutamide and subsequent covalent binding to cellular proteins responsible its toxicity. A novel N-S glutathione adduct identified previous study (Kang et al., 2007). Due extensive first pass metabolism, metabolites such as 2-hydroxyflutamide 4-nitro-3-(trifluoromethyl)phenylamine (Flu-1) have...
Nirmatrelvir and GC373 inhibit the SARS-CoV-2 3CL protease hinder viral replication in COVID-19. As nirmatrelvir Paxlovid is oxidized by cytochrome P450 3A4, ritonavir coadministered to block this. However, undesirably alters metabolism of other drugs. Hydrogens can be replaced with deuterium slow oxidation. Results show that slows oxidation adjacent nitrogen ∼40% type warhead switch site oxidative metabolism.
ADVERTISEMENT RETURN TO ISSUEPREVNoteNEXTSynthesis of 3-Methoxycarbonylmethyl Derivatives Dihydroquinolone and DihydrochromenoneJames A. Nieman Michael D. EnnisView Author Information Structural, Analytical & Medicinal Chemistry, Pharmacia Corp., Kalamazoo, Michigan 49001 [email protected]Cite this: J. Org. Chem. 2001, 66, 6, 2175–2177Publication Date (Web):February 17, 2001Publication History Received27 October 2000Published online17 February 2001Published inissue 1 March...
This study explores the relationship between structural alterations of nirmatrelvir, such as homologation and deuteration, metabolic stability newly synthesized derivatives. We developed a reliable synthetic protocol toward dideutero-nirmatrelvir its homologated analogues with high isotopic incorporation. Deuteration primary site nirmatrelvir provides 3-fold improvement human microsomal but is accompanied by an increased metabolism rate at secondary sites. Homologation lactam ring allows...
Abstract A four step highly stereoselective synthesis of (±)-cis,cis-spir0[4.4]nonane-1,6diol (4) in 55% overall yield is described detail beginning with ethyl 2-oxocyclopentanecarboxylate. new resolution diol (±) using (1R)-(+)-camphor also reported.
A new method for the preparation of 3,4- and 2,5-disubstituted furan rings is described. variety 2-silylated-3-(hydroxymethyl)furans 2-silylated-3-furoic acids lithiate exclusively at C-4 when treated with 2.2 equivs BuLi. The resulting dianions were quenched a electrophiles to provide 2-silylated-3-(hydroxymethyl)-4-substituted furans 2-silylated-4-substituted 3-furoic in good excellent yields. Removal silyl group (n-Bu4NF) provided 4-substituted-3-(hydroxymethyl)furans methyl...