A5037635472- Migraine and Headache Studies
- Chemical Synthesis and Analysis
- Neuropeptides and Animal Physiology
- Peptidase Inhibition and Analysis
- Trigeminal Neuralgia and Treatments
- Stress Responses and Cortisol
- Crystallization and Solubility Studies
- Wnt/β-catenin signaling in development and cancer
- X-ray Diffraction in Crystallography
- Monoclonal and Polyclonal Antibodies Research
- Porphyrin and Phthalocyanine Chemistry
- Tryptophan and brain disorders
- Cancer therapeutics and mechanisms
- Asymmetric Hydrogenation and Catalysis
- Chemical synthesis and alkaloids
- Click Chemistry and Applications
- Metal complexes synthesis and properties
- Asymmetric Synthesis and Catalysis
- Cholinesterase and Neurodegenerative Diseases
- Chemical Synthesis and Reactions
- Signaling Pathways in Disease
- Cancer, Hypoxia, and Metabolism
- Nicotinic Acetylcholine Receptors Study
- Cancer Treatment and Pharmacology
- Bioactive Compounds and Antitumor Agents
Biohaven Pharmaceuticals (United States)
2019-2024
Bristol-Myers Squibb (United States)
2009-2023
Bristol-Myers Squibb (Germany)
1995-2023
Wallingford Public Library
2003
Princeton University
1985-1987
The anticancer drug doxorubicin (DOX) has been linked to chimeric BR96, an internalizing monoclonal antibody that binds a Lewis(y)-related, tumor-associated antigen, through two lysosomally cleavable dipeptides, Phe-Lys and Val-Cit, giving immunoconjugates 72 73. A self-immolative p-aminobenzyloxycarbonyl (PABC) spacer between the dipeptides DOX was required for rapid quantitative generation of free drug. release from model substrate Z-Phe-Lys-PABC-DOX 49 30-fold faster than...
Calcitonin gene-related peptide receptor has been implicated in the pathogenesis of migraine. Rimegepant is an orally administered, small-molecule, calcitonin antagonist that may be effective acute migraine treatment.In a multicenter, double-blind, phase 3 trial, we randomly assigned adults with at least 1-year history and two to eight attacks moderate or severe intensity per month receive rimegepant dose 75 mg matching placebo for treatment single attack. The primary end points were freedom...
Controlled lysosomal rupture was initiated in lysosome‐rich, macrophage‐like cells by the synthetic lysosomotropic detergent, O ‐methyl‐serine dodecylamide hydrochloride (MSDH). When MSDH applied at low concentrations, resulting partial rupture, activation of pro‐caspase‐3‐like proteases and apoptosis followed after some hours. Early during apoptosis, but clearly secondary to destabilization, mitochondrial transmembrane potential declined. At high caused extensive necrosis. It is suggested...
High mole ratio BR96 immunoconjugates were synthesized using branched peptide-doxorubicin linkers designed to liberate doxorubicin following antigen-specific internalization into lysosomes. However, these are highly prone noncovalent, dimeric aggregation. We hypothesize that this is due (1) the hydrophobic nature of peptides, (2) loss positive charge upon amide formation at 3'-amino group doxorubicin, and (3) proximity peptide residues form efficient intermolecular stacking interactions. By...
ADVERTISEMENT RETURN TO ISSUEPREVArticleNEXTA new EGF-active polymeric pyridinium alkaloid from the sponge Callyspongia fibrosaMichael T. Davies-Coleman, D. John Faulkner, Gene M. Dubowchik, Gregory P. Roth, Craig Polson, and FairchildCite this: J. Org. Chem. 1993, 58, 22, 5925–5930Publication Date (Print):October 1, 1993Publication History Published online1 May 2002Published inissue 1 October...
Calcitonin gene-related peptide (CGRP) receptor antagonists have demonstrated clinical efficacy in the treatment of acute migraine. Herein, we describe design, synthesis, and preclinical characterization a highly potent, oral CGRP antagonist BMS-927711 (8). Compound 8 has good bioavailability rat cynomolgus monkey, attractive overall properties, shows dose-dependent activity primate model CGRP-induced facial blood flow. is presently phase II trials.
GSK-3 is a serine/threonine kinase that has numerous substrates. Many of these proteins are involved in the regulation diverse cellular functions, including metabolism, differentiation, proliferation, and apoptosis. Inhibition may be useful treating number diseases Alzheimer's disease (AD), type II diabetes, mood disorders, some cancers, but approach poses significant challenges. Here, we present class isonicotinamides potent, highly kinase-selective inhibitors, members which demonstrated...
[structure: see text] 2-Aryl-2,2-difluoroacetamido-proline and pipecolate esters are high affinity FKBP12 ligands whose rotamase inhibitory activity is comparable to that seen for the corresponding ketoamides. X-ray structural studies suggest fluorine atoms participate in discrete interactions with Phe36 phenyl ring Tyr26 hydroxyl group, latter resembling a moderate-to-weak hydrogen bond.
Glycogen synthase kinase-3 (GSK-3) is a serine/threonine kinase that regulates numerous cellular processes, including metabolism, proliferation, and cell survival. Due to its multifaceted role, GSK-3 has been implicated in variety of diseases, Alzheimer's disease, type 2 diabetes, cancer, mood disorders. GSK-3β linked the formation neurofibrillary tangles associated with disease arise from hyperphosphorylation tau protein. The design synthesis series imidazo[1,2-b]pyridazine derivatives were...
Indazoles are regioselectively protected at N-2 by a 2-(trimethylsilyl)ethoxymethyl (SEM) group using novel conditions. The SEM can efficiently direct regioselective C-3 lithiation, and the resulting nucleophile react with wide range of electrophiles to generate indazole derivatives. be removed treatment TBAF in THF or aqueous HCl EtOH.
Calcitonin gene-related peptide (CGRP) has been implicated in the pathogenesis of migraine. Early chemistry leads suffered from modest potency, significant CYP3A4 inhibition, and poor aqueous solubility. Herein, we describe optimization these to give 4 (BMS-694153), a molecule with outstanding favorable predictive toxicology profile, remarkable Compound good intranasal bioavailablity rabbits shows dose-dependent activity validated vivo ex migraine models.
Calcitonin gene-related peptide (CGRP) receptor antagonists have been clinically shown to be effective in the treatment of migraine, but identification potent and orally bioavailable compounds has challenging. Herein, we describe conceptualization, synthesis, preclinical characterization a potent, active CGRP antagonist 5 (BMS-846372). Compound good oral bioavailability rat, dog, cynomolgus monkeys overall attractive properties including strong (>50% inhibition) exposure-dependent vivo...
FKBP12 is best known as the target of widely used immunosuppressive drug FK506 but may also play a role in neuronal survival. Nonimmunosuppressive ligands have been shown to neuroprotective and neuroregenerative activity both vitro vivo, stimulating interest development high-throughput screens rapidly identify novel ligands. was expressed His(6)-fusion bacteria purified by metal ion affinity gel filtration chromatography. A fluorescence polarization assay developed FKBP12. Dissociation...
Glycogen synthase kinase-3 (GSK-3) is a serine/threonine kinase that serves as an important regulator of broad range cellular functions. It has been linked to Alzheimer's disease well various other diseases, including mood disorders, type 2 diabetes, and cancer. There considerable evidence indicating GSK-3β in the central nervous system plays role production abnormal, hyperphosphorylated, microtubule-associated tau protein found neurofibrillary tangles associated with disease. A series...