A5071771766- Antibiotic Resistance in Bacteria
- Antibiotics Pharmacokinetics and Efficacy
- Pneumocystis jirovecii pneumonia detection and treatment
- Antimicrobial Resistance in Staphylococcus
- Chemical Synthesis and Analysis
- Cancer therapeutics and mechanisms
- Microbial Natural Products and Biosynthesis
- Synthesis and Biological Activity
- HIV/AIDS drug development and treatment
- Bioactive Compounds and Antitumor Agents
- Plant Disease Resistance and Genetics
- Phenothiazines and Benzothiazines Synthesis and Activities
- Coccidia and coccidiosis research
- Synthesis and Reactions of Organic Compounds
- Asymmetric Hydrogenation and Catalysis
- Tuberculosis Research and Epidemiology
- Hepatitis C virus research
- Carbohydrate Chemistry and Synthesis
- Innovative Microfluidic and Catalytic Techniques Innovation
- Microbial infections and disease research
- Organophosphorus compounds synthesis
- Microbial Metabolism and Applications
- Synthesis and Biological Evaluation
- Natural product bioactivities and synthesis
- Cyclopropane Reaction Mechanisms
Mapp Biopharmaceutical (United States)
2019-2022
Doctors Company (United States)
2018
Torrey Pines Institute For Molecular Studies
2007-2009
Essential Research (United States)
2002-2003
La Roche College
2003
Microcide (United States)
1998-2000
Pfizer (United States)
1987-1998
ABSTRACT Whole-cell assays were implemented to search for efflux pump inhibitors (EPIs) of the three multidrug resistance pumps (MexAB-OprM, MexCD-OprJ, MexEF-OprN) that contribute fluoroquinolone in clinical isolates Pseudomonas aeruginosa . Secondary developed identify lead compounds with exquisite activities as inhibitors. A broad-spectrum EPI which is active against all known Mex from P. and their close Escherichia coli homolog (AcrAB-TolC) was discovered. When this compound, MC-207,110,...
ADVERTISEMENT RETURN TO ISSUEPREVPerspectiveNEXTProdrugs of Phosphates and PhosphonatesScott J. Hecker* Mark D. ErionView Author Information Metabasis Therapeutics, Inc., 11119 North Torrey Pines Road, La Jolla, California 92037* To whom correspondence should be addressed. Phone: 858-622-3910 . Fax: 858-622-5583. E-mail: [email protected]Cite this: Med. Chem. 2008, 51, 8, 2328–2345Publication Date (Web):February 1, 2008Publication History Received5 October 2007Published online1 February...
The increasing dissemination of carbapenemases in Gram-negative bacteria has threatened the clinical usefulness β-lactam class antimicrobials. A program was initiated to discover a new series serine β-lactamase inhibitors containing boronic acid pharmacophore, with goal finding potent inhibitor carbapenemase enzymes that are currently compromising utility carbapenem antibacterials. Potential lead structures were screened silico by modeling into active sites key β-lactamases. Promising...
Despite major advances in the β-lactamase inhibitor field, certain enzymes remain refractory to inhibition by agents recently introduced. Most important among these are class B (metallo) enzyme NDM-1 of Enterobacteriaceae and D (OXA) Acinetobacter baumannii. Continuing boronic acid program that led vaborbactam, efforts were directed toward expanding spectrum allow treatment a wider range organisms. Through key structural modifications bicyclic lead, stepwise gains achieved, ultimately...
Abstract The emergence of multidrug-resistant (MDR) Gram-negative pathogens is an urgent global medical challenge. old polymyxin lipopeptide antibiotics (polymyxin B and colistin) are often the only therapeutic option due to resistance all other classes lean antibiotic drug development pipeline. However, colistin suffer from major issues in safety (dose-limiting nephrotoxicity, acute toxicity), pharmacokinetics (poor exposure lungs) efficacy (negligible activity against pulmonary infections)...
ADVERTISEMENT RETURN TO ISSUEPREVLetterNEXTInhibitors of Efflux Pumps in Pseudomonas aeruginosa Potentiate the Activity Fluoroquinolone Antibacterial LevofloxacinThomas E. Renau, Roger Léger, Eric M. Flamme, Joan Sangalang, Miles W. She, Rose Yen, Carla L. Gannon, David Griffith, Suzanne Chamberland, Olga Lomovskaya, Scott J. Hecker, Ving Lee, Toshiharu Ohta, and Kiyoshi NakayamaView Author Information Microcide Pharmaceuticals Inc., 850 Maude Avenue, Mountain View, California 94043, New...
A simple method for the conversion of carboxylic acids to boronic esters via redox-active (RAEs) is reported using copper catalysis. The scope this transformation broad, and compared with known protocols available, it represents most inexpensive, rapid, operationally option. In addition a full exploration scope, kinetic study was performed elucidate substrate reagent concentration dependences.
Quantitative structure-activity relationships have been found among macrolide antibacterial agents in their potencies against the bacterial pathogen Pasteurella multocida both vitro and mouse infections. To obtain these we measured, other things, pK(a)'s log P's of 15 known macrolides diverse structures. Among compounds, potency [log(1/MIC)] is a function P, D, CMR (R = 0.86). In vivo higher pK(a), HPLC chromatographic capacity factor k', log(1/MIC) pNF 0.93). defined as negative logarithm...
AMP-activated protein kinase (AMPK) is a heterotrimeric that regulates cellular energy metabolism by affecting energy-consuming pathways such as de novo lipid biosynthesis and glucose production well energy-producing oxidation uptake. Accordingly, compounds activate AMPK represent potential drug candidates for the treatment of hyperlipidemia type 2 diabetes. Screening proprietary library AMP mimetics identified phosphonic acid bears little structural resemblance to but capable activating...
Phosphonic acid (PA) thyroid hormone receptor (TR) agonists were synthesized to exploit the poor distribution of PA-based drugs extrahepatic tissues and thereby improve therapeutic index. Nine PAs showed excellent TR binding affinities (TRβ1, Ki < 10 nM), most them demonstrated significant cholesterol lowering effects in a cholesterol-fed rat (CFR) model. Unlike corresponding carboxylic analogue T3, PA 22c liver-selective by inducing maximal mitochondrial glycerol-3-phosphate dehydrogenase...
Within this paper, we present the design, development, and scale-up of a process for continuous Matteson reaction to produce key intermediate toward β-lactamase inhibitor vaborbactam. This includes successful implementation concept at multiton production scale API Patheon, part Thermo Fisher Scientific. The first-generation flow with its discontinuous downstream processing was further developed fully through installation loop reactor. enabled increased productivity energy efficiency,...
ADVERTISEMENT RETURN TO ISSUEPREVArticleNEXTTotal synthesis of (+)-dihydromevinolinScott J. Hecker and Clayton H. HeathcockCite this: Am. Chem. Soc. 1986, 108, 15, 4586–4594Publication Date (Print):July 1, 1986Publication History Published online1 May 2002Published inissue 1 July 1986https://pubs.acs.org/doi/10.1021/ja00275a053https://doi.org/10.1021/ja00275a053research-articleACS PublicationsRequest reuse permissionsArticle Views1310Altmetric-Citations45LEARN ABOUT THESE METRICSArticle...
ADVERTISEMENT RETURN TO ISSUEPREVArticleNEXTSynthesis of compounds designed to inhibit bacterial cell wall transglycosylationScott J. Hecker, Martha L. Minich, and Karen LackeyCite this: Org. Chem. 1990, 55, 16, 4904–4911Publication Date (Print):August 1, 1990Publication History Published online1 May 2002Published inissue 1 August 1990https://pubs.acs.org/doi/10.1021/jo00303a028https://doi.org/10.1021/jo00303a028research-articleACS PublicationsRequest reuse permissionsArticle...
ADVERTISEMENT RETURN TO ISSUEPREVArticleNEXTTotal synthesis and biological evaluation of structural analogs compactin dihydromevinolinClayton H. Heathcock, Cheri R. Hadley, Terry Rosen, Peter D. Theisen, Scott J. HeckerCite this: Med. Chem. 1987, 30, 10, 1858–1873Publication Date (Print):October 1, 1987Publication History Published online1 May 2002Published inissue 1 October 1987https://pubs.acs.org/doi/10.1021/jm00393a030https://doi.org/10.1021/jm00393a030research-articleACS...
Bromine induced lactamization of vinyl acetohydroxamates facilitated syntheses monocyclic β-lactams suitable for incorporation a thiomethyl and extended functionality at the C(4) position. Elaboration resulting substituted N-hydroxy-2-azetidinones allowed functionalized α-amino substituents appropriate enhancement antibiotic activity. Evaluation antibacterial activity against panel Gram-positive Gram-negative bacteria revealed structure-activity relationships (SAR) identification potent new...
Hydrogenation of the C(4') exocyclic olefin pacidamycins has been shown to produce a series semisynthetic compounds, dihydropacidamycins, with antimicrobial activity similar that natural products. Elucidation stereochemistry in completed through campaign product degradation experiments combination total synthesis lowest-molecular weight dihydropacidamycin, dihydropacidamycin D. The stereochemical identities tryptophan and two alanine residues contained pacidamycin D have be (S)...
2'-C-Methyladenosine exhibits impressive inhibitory activity in the cell-based hepatitis C virus (HCV) subgenomic replicon assay, by virtue of intracellular conversion to corresponding nucleoside triphosphate (NTP) and inhibition NS5B RNA-dependent RNA polymerase (RdRp). However, rapid degradation adenosine deaminase (ADA) limits its overall therapeutic potential. To reduce ADA-mediated deamination, we prepared cyclic 1-aryl-1,3-propanyl prodrugs monophosphate (NMP), anticipating cytochrome...
In recognition of the need for effective oral therapies to treat Gram-negative bacterial infections, efforts were directed toward identifying an prodrug β-lactamase inhibitor clinical candidate QPX7728. Seventeen prodrugs synthesized; key properties investigated rates cleavage active form in vitro, pharmacokinetics across species, and crystallinity. Compound 5-Na (QPX7831 Sodium) emerged with optimal all attributes.
ADVERTISEMENT RETURN TO ISSUEPREVArticleNEXTNew total synthesis of (.+-.)-indolmycinJohn P. Dirlam, David A. Clark, and Scott J. HeckerCite this: Org. Chem. 1986, 51, 25, 4920–4924Publication Date (Print):December 1, 1986Publication History Published online1 May 2002Published inissue 1 December 1986https://pubs.acs.org/doi/10.1021/jo00375a030https://doi.org/10.1021/jo00375a030research-articleACS PublicationsRequest reuse permissionsArticle Views855Altmetric-Citations34LEARN ABOUT THESE...
Hepatitis C virus (HCV) infects an estimated 170 million individuals worldwide, and the current standard of care, a combination pegylated interferon alpha ribavirin, is efficacious in achieving sustained viral response ~50% treated patients. Novel therapies under investigation include use nucleoside analog inhibitors RNA-dependent RNA polymerase. NM283, 3'-valyl ester prodrug 2'-C-methylcytidine, has demonstrated antiviral efficacy HCV-infected patients (N. Afdhal et al., J. Hepatol....
We have developed a convenient development-scale reactor (0.44 mol/h) to prepare diazomethane from N-methyl-N-nitroso-p-toluenesulfonamide (MNTS) in ∼80% yield. Diazomethane (CH2N2) made with this is extracted into nitrogen gas the liquid reaction mixture, effectively removing it reagents and byproducts that may interfere subsequent reactions. Vertically oriented tubular reactors were used produce consume situ. Key features of include high productivity correspondingly low volume (reactor...
We report the scalable, high-yielding, and highly selective synthesis of β-lactamase inhibitor QPX7728 featuring two key synthetic steps: nickel-catalyzed boron insertion benzofuran 1 followed by enantioselective cyclopropanation resulting cyclic vinylboronate 2. The identification reagents (catalyst chiral auxiliary) for both steps relied on use high-throughput experimentation. Further optimization allowed cost-effective scalable production QPX7728.