A5085288108- Chemical Synthesis and Analysis
- Asymmetric Hydrogenation and Catalysis
- Microwave-Assisted Synthesis and Applications
- Multicomponent Synthesis of Heterocycles
- Asymmetric Synthesis and Catalysis
- Cell Adhesion Molecules Research
- Malaria Research and Control
- Trypanosoma species research and implications
- Mosquito-borne diseases and control
- Surface Chemistry and Catalysis
- Analytical Chemistry and Chromatography
- Computational Drug Discovery Methods
- Catalysis and Hydrodesulfurization Studies
- Chemical Reactions and Isotopes
- Synthesis and Catalytic Reactions
- Synthetic Organic Chemistry Methods
- Synthesis and Biological Evaluation
- Peptidase Inhibition and Analysis
- Chemokine receptors and signaling
- Chronic Lymphocytic Leukemia Research
- Ion channel regulation and function
- Organophosphorus compounds synthesis
- Traditional and Medicinal Uses of Annonaceae
- Melanoma and MAPK Pathways
- Research on Leishmaniasis Studies
Novartis (United States)
2021-2024
Novartis (Switzerland)
2020
Boehringer Ingelheim (United States)
2001-2018
University of California, Santa Barbara
1994-2014
Boehringer Ingelheim (Canada)
2006
Princeton University
2005
University of South Carolina
1997
The Ohio State University
1997
Dengue virus (DENV) is a mosquito-borne flavivirus that poses threat to public health, yet no antiviral drug available. We performed high-throughput phenotypic screen using the Novartis compound library and identified candidate chemical inhibitors of DENV. This series was optimized improve properties such as anti-DENV potency solubility. The lead compound, NITD-688, showed strong against all four serotypes DENV demonstrated excellent oral efficacy in infected AG129 mice. There 1.44-log...
Millions who live in Latin America and sub-Saharan Africa are at risk of trypanosomatid infections, which cause Chagas disease human African trypanosomiasis (HAT). Improved HAT treatments available, but therapies rely on two nitroheterocycles, suffer from lengthy drug regimens safety concerns that frequent treatment discontinuation. We performed phenotypic screening against trypanosomes identified a class cyanotriazoles (CTs) with potent trypanocidal activity both vitro mouse models HAT....
A series of synthetic transformations were successfully and safely scaled up to multigram quantities using focused microwave irradiation with a continuous flow reaction cell that was developed in-house which can be easily adapted commercially available instrumentation. The representative reactions investigated included aromatic nucleophilic substitution (SNAr), esterification, the Suzuki cross-coupling reaction. In general, product yields equivalent or greater than those run under...
A series of 5-aryl-2-amino-imidazothiadiazole (ITD) derivatives were identified by a phenotype-based high-throughput screening using blood stage Plasmodium falciparum (Pf) growth inhibition assay. lead optimization program focused on improving antiplasmodium potency, selectivity against human kinases, and absorption, distribution, metabolism, excretion, toxicity properties extended pharmacological profiles culminated in the identification INE963 (1), which demonstrates potent cellular...
ADVERTISEMENT RETURN TO ISSUEPREVArticleNEXTTADDOL-Based Titanium Catalysts and Their Adducts: Understanding Asymmetric Catalysis of Diels-Alder ReactionsCornelius Haase, Christopher R. Sarko, Marcello DiMareCite this: J. Org. Chem. 1995, 60, 6, 1777–1787Publication Date (Print):March 1, 1995Publication History Published online1 May 2002Published inissue 1 March 1995https://pubs.acs.org/doi/10.1021/jo00111a041https://doi.org/10.1021/jo00111a041research-articleACS PublicationsRequest reuse...
High-throughput screening is routinely employed as a method for the identification of novel hit structures. Large numbers active compounds are typically procured in this way and must undergo rigorous validation process. This process described detail collection hits identified inhibitors IκB kinase-β (IKKβ), key regulatory enzyme nuclear factor-κB (NF-κB) pathway. From these studies, promising series was selected. Subsequent lead generation activities included development pharmacophore...
Diarrhoeal disease caused by Cryptosporidium is a major cause of morbidity and mortality in young malnourished children from low- middle-income countries, with no vaccine or effective treatment. Here we describe the discovery EDI048, PI(4)K inhibitor, designed to be active at infection site gastrointestinal tract undergo rapid metabolism liver. By using mutational analysis crystal structure, show that EDI048 binds highly conserved amino acid residues ATP-binding site. orally efficacious an...
Human African Trypanosomiasis (HAT) is a vector-borne disease caused by kinetoplastid parasites of the Trypanosoma genus. The proceeds in two stages, with hemolymphatic blood stage and meningo-encephalic brain stage. In latter stage, parasite causes irreversible damage to leading sleep cycle disruption fatal if untreated. An orally bioavailable treatment highly desirable. this study, we present brain-penetrant, parasite-selective 20S proteasome inhibitor that was rapidly optimized from an...
Syn-selective reduction protocols for β-hydroxy ketones are described exploiting the intermediacy of titanium and boron chelates derived from TiCl4 BCl3, respectively. Reductions conducted at −78 °C in CH2Cl2 using a wide range CH2Cl2-soluble reducing agents. Added acid-scavenging agents detrimental to reaction selectivity. An A(1,3)-like interaction involving stereocenter responsible asymmetric induction provides conformational biasing intermediate necessary high diastereoselectivity.
The COVID-19 pandemic highlights the ongoing risk of zoonotic transmission coronaviruses to global health. To prepare for future pandemics, it is essential develop effective antivirals targeting a broad range coronaviruses. Targeting and clinically validated coronavirus main protease (M
ADVERTISEMENT RETURN TO ISSUEPREVArticleNEXTChelation-controlled protocol for the diastereoselective reduction of ketonesChristopher R. Sarko, Ian C. Guch, and Marcello DiMareCite this: J. Org. Chem. 1994, 59, 4, 705–706Publication Date (Print):February 1, 1994Publication History Published online1 May 2002Published inissue 1 February 1994https://pubs.acs.org/doi/10.1021/jo00083a004https://doi.org/10.1021/jo00083a004research-articleACS PublicationsRequest reuse permissionsArticle...
A synthesis of the first-in-class pan-serotype dengue virus inhibitor NITD-688 is presented. The Gewald reaction N-(tert-butoxycarbonyl)-6,6-dimethylpiperidin-3-one with malononitrile and sulfur in presence l-proline as a catalyst gave tert-butyl 2-amino-3-cyano-6,6-dimethyl-6,7-dihydrothieno[3,2-c]pyridine-5(4H)-carboxylate. This was coupled [4-(aminosulfonyl)phenyl]acetic acid by using propanephosphonic anhydride. subsequent reductive alkylation cyclohexanecarboxaldehyde NITD-688....