A5037746003- Chemical Synthesis and Analysis
- Click Chemistry and Applications
- Alzheimer's disease research and treatments
- Cancer therapeutics and mechanisms
- Computational Drug Discovery Methods
- Cannabis and Cannabinoid Research
- DNA and Nucleic Acid Chemistry
- Drug Transport and Resistance Mechanisms
- Receptor Mechanisms and Signaling
- Pharmacological Receptor Mechanisms and Effects
- Cholinesterase and Neurodegenerative Diseases
- Synthesis and Biological Evaluation
- Antibiotic Resistance in Bacteria
- Monoclonal and Polyclonal Antibodies Research
- Pancreatic function and diabetes
- Bioactive Compounds and Antitumor Agents
- Advanced biosensing and bioanalysis techniques
- Neuroscience and Neuropharmacology Research
- Forensic Toxicology and Drug Analysis
- Protein Degradation and Inhibitors
- Synthesis and Catalytic Reactions
- Neurotransmitter Receptor Influence on Behavior
- Synthesis and Reactions of Organic Compounds
- RNA and protein synthesis mechanisms
- Crystallization and Solubility Studies
Biogen (United States)
2021-2025
Pfizer (United States)
2012-2024
Sichuan University
2021
Technische Universität Braunschweig
2021
University of Oregon
2021
University of Messina
2021
Vrije Universiteit Brussel
2021
Massachusetts Institute of Technology
2021
Universidade Nova de Lisboa
2021
Chengdu Normal University
2021
This article presents several covalent inhibitors, including examples of successful drugs, as well highly selective, irreversible inhibitors emerging therapeutic targets, such fatty acid amide hydolase. Covalent have many desirable features, increased biochemical efficiency target disruption, less sensitivity toward pharmacokinetic parameters and duration action that outlasts the pharmacokinetics compound. Safety concerns must be mitigated include lack specificity potential immunogenicity...
Abstract We review here studies defining the DNA alkylation properties of a class potent antitumor antibiotics that includes CC‐1065 and duocarmycins, as well investigations delineate fundamental relationships between their structure, functional reactivity, biological properties. In conjunction with study natural products themselves, examination synthetic agents containing deep‐seated structural changes, unnatural enantiomers products, related analogs has defined basis for sequence selective...
The endogenous cannabinoid (endocannabinoid) anandamide is principally degraded by the integral membrane enzyme fatty acid amide hydrolase (FAAH). Pharmacological blockade of FAAH has emerged as a potentially attractive strategy for augmenting endocannabinoid signaling and retaining beneficial effects receptor activation, while avoiding undesirable side effects, such weight gain impairments in cognition motor control, observed with direct 1 agonists. Here, we report detailed mechanistic...
Fatty acid amide hydrolase (FAAH) is an integral membrane enzyme that degrades the fatty family of signaling lipids, including endocannabinoid anandamide. Genetic or pharmacological inactivation FAAH leads to analgesic, anti-inflammatory, anxiolytic, and antidepressant phenotypes in rodents without showing undesirable side effects observed with direct cannabinoid receptor agonists, indicating may represent attractive therapeutic target for treatment pain, inflammation, other central nervous...
Fatty acid amide hydrolase (FAAH) is an integral membrane serine that degrades the fatty family of signaling lipids, including endocannabinoid anandamide. Genetic or pharmacological inactivation FAAH leads to analgesic and anti-inflammatory phenotypes in rodents without showing undesirable side effects observed with direct cannabinoid receptor agonists, indicating may represent attractive therapeutic target for treatment inflammatory pain other nervous system disorders. Herein, we report...
BACKGROUND: Fatty acid amide hydrolase (FAAH) is an integral membrane enzyme that hydrolyzes the endocannabinoid anandamide and related amidated signaling lipids. Genetic or pharmacological inactivation of FAAH produces analgesic, anti-inflammatory, anxiolytic, antidepressant phenotypes without showing undesirable side effects direct cannabinoid receptor agonists, indicating may be a promising therapeutic target. OBJECTIVES: This review highlights advances in development inhibitors different...
Bioorthogonal reactions, including the strain-promoted azide-alkyne cycloaddition (SPAAC) and inverse electron demand Diels-Alder (iEDDA) have become increasingly popular for live-cell imaging applications. However, stability reactivity of reagents has never been systematically explored in context a living cell. Here we report universal, organelle-targetable system based on HaloTag protein technology directly comparing bioorthogonal reagent reactivity, specificity, using clickable ligands...
The cytotoxic action of the antitumor antibiotic mitomycin C occurs primarily at level DNA. Using highly sensitive fluorescence assays which depend on enhancement ethidium only when it intercalates duplex regions DNA, three aspects DNA have been studied: (a) cross-linking events, (b) alkylation without necessarily cross-linking, and (c) strand breakage. Cross-linking is determined by return after a heat denaturation step alkaline pH's. Under these conditions denatured gives no fluorescence....
The integral membrane enzyme fatty acid amide hydrolase (FAAH) hydrolyzes the endocannabinoid anandamide and related amidated signaling lipids. Genetic or pharmacological inactivation of FAAH produces analgesic, anxiolytic, antiinflammatory phenotypes but not undesirable side effects direct cannabinoid receptor agonists, indicating that may be a promising therapeutic target. Structure-based inhibitor design has, however, been hampered by difficulties in expressing human enzyme. Here, we...
PF-06651600 was developed as an irreversible inhibitor of JAK3 with selectivity over the other three JAK isoforms. A high level toward is achieved by covalent interaction a unique cysteine residue (Cys-909) in catalytic domain JAK3, which replaced serine Importantly, 10 kinases kinome have at equivalent position Cys-909 JAK3. Five those belong to TEC kinase family including BTK, BMX, ITK, RLK, and are also inhibited PF-06651600. Preclinical data demonstrate that inhibition cytolytic function...
γ-Secretase is an intramembrane aspartyl protease that cleaves the amyloid precursor protein to produce neurotoxic β-amyloid peptides (i.e. Aβ42) have been implicated in pathogenesis of Alzheimer disease. Small molecule γ-secretase modulators (GSMs) emerged as potential disease-modifying treatments for disease because they reduce formation Aβ42 while not blocking processing substrates. We developed clickable GSM photoaffinity probes with goal identifying target various classes GSMs and...
[Cu(S,S)-t-Bu-box](OTf)2 (1) catalyzes the enantioselective amination of enolsilanes with azodicarboxylate derivatives. Isomerically pure aryl ketones, acylpyrroles, and thioesters added to azo-imide in greater than 95% ee. The use an alcohol additive was critical achieving catalyst turnover.
The "Notch-sparing" γ-secretase inhibitor (GSI) BMS-708,163 (Avagacestat) is currently in phase II clinical trials for Alzheimer's disease. Unlike previously failed GSIs, considered to be a promising drug candidate because of its reported Notch-sparing activity the inhibition Aβ production over Notch cleavage. We now report that binds directly presenilin-1 N-terminal fragment and binding can challenged by other pan-GSIs, but not modulators. Furthermore, blocks four different active...
Chinese hamster ovary (CHO) cells are often used to produce therapeutic monoclonal antibodies (mAbs). CHO express many host cell proteins (HCPs) required for their growth. Interactions of HCPs with mAbs can sometimes result in co-purification trace levels 'hitchhiker' during the manufacturing process. Purified mAb-1 product produced early stages process optimization had high HCP levels. In addition, these lots formed delayed-onset particles containing and its heavy chain C-terminal...
Inhibition of β-secretase BACE1 is considered one the most promising approaches for treating Alzheimer's disease. Several structurally distinct inhibitors have been withdrawn from development after inducing ocular toxicity in animal models, but target mediating this has not identified. Here we use a clickable photoaffinity probe to identify cathepsin D (CatD) as principal off-target human cells. We find that several blocked CatD activity cells with much greater potency than displayed...
Monoacylglycerol lipase (MAGL) is the main enzyme responsible for degradation of endocannabinoid 2-arachidonoylglycerol (2-AG) in CNS. MAGL catalyzes conversion 2-AG to arachidonic acid (AA), a precursor proinflammatory eicosannoids such as prostaglandins. Herein we describe highly efficient inhibitors, identified through parallel medicinal chemistry approach that highlighted improved efficiency azetidine and piperidine-derived carbamates. The discovery optimization 3-substituted carbamate...
Monoacylglycerol lipase (MAGL) inhibition provides a potential treatment approach to neuroinflammation through modulation of both the endocannabinoid pathway and arachidonoyl signaling in central nervous system (CNS). Herein we report discovery compound 15 (PF-06795071), potent selective covalent MAGL inhibitor, featuring novel trifluoromethyl glycol leaving group that confers significant physicochemical property improvements as compared with earlier inhibitor series more lipophilic groups....
Multiple sclerosis (MS) is a chronic disease with an underlying pathology characterized by inflammation-driven neuronal loss, axonal injury, and demyelination. Bruton's tyrosine kinase (BTK), nonreceptor member of the TEC family kinases, involved in regulation, migration, functional activation B cells myeloid periphery central nervous system (CNS), cell types which are deemed to contributing progression MS patients. Herein, we describe discovery BIIB129 (25), structurally distinct...
ADVERTISEMENT RETURN TO ISSUEPREVArticleNEXT(+)- and ent-(-)-Duocarmycin SA (+)- ent-(-)-N-BOC-DSA DNA Alkylation Properties.Alkylation Site Models That Accommodate the Offset AT-Rich Adenine N3 Selectivity of Enantiomeric AgentsDale L. Boger, Douglas S. Johnson, Weiya YunCite this: J. Am. Chem. Soc. 1994, 116, 5, 1635–1656Publication Date (Print):March 1, 1994Publication History Published online1 May 2002Published inissue 1 March...
ADVERTISEMENT RETURN TO ISSUEPREVArticleNEXTAlkyne insertion reactions of metal-carbenes derived from enynyl-.alpha.-diazoketones [R'CN2COCR2CH2C.tplbond.C(CH2)n-2CH:CH2]Thomas R. Hoye, Christopher J. Dinsmore, Douglas S. Johnson, and Paul F. KorkowskiCite this: Org. Chem. 1990, 55, 15, 4518–4520Publication Date (Print):July 1, 1990Publication History Published online1 May 2002Published inissue 1 July...