A5064543162- Neuroscience and Neuropharmacology Research
- Monoclonal and Polyclonal Antibodies Research
- X-ray Diffraction in Crystallography
- Crystallization and Solubility Studies
- Chemical Synthesis and Analysis
- Nicotinic Acetylcholine Receptors Study
- Peptidase Inhibition and Analysis
- Synthesis and Biological Evaluation
- Receptor Mechanisms and Signaling
- Phenothiazines and Benzothiazines Synthesis and Activities
- Pharmacological Receptor Mechanisms and Effects
- Radiopharmaceutical Chemistry and Applications
- Treatment of Major Depression
- Neurotransmitter Receptor Influence on Behavior
- Glycosylation and Glycoproteins Research
- Advanced biosensing and bioanalysis techniques
- Coordination Chemistry and Organometallics
- Click Chemistry and Applications
- DNA and Nucleic Acid Chemistry
- Cancer therapeutics and mechanisms
- Fungal Infections and Studies
- HER2/EGFR in Cancer Research
- Memory and Neural Mechanisms
- Synthesis and Reactivity of Heterocycles
- Bioactive Compounds and Antitumor Agents
Bristol-Myers Squibb (United States)
2008-2020
Bristol-Myers Squibb (Germany)
1997-2017
Circle (United States)
2014
University of Florida
1984
A strategy for covalent modification of monoclonal antibodies utilizing the oxidized oligosaccharide moieties on molecule was evaluated and compared to more conventional methods. As judged by quantitative in vitro measurements, a antibody conjugate prepared via oligosaccharides retained homogeneous antigen binding property affinity unmodified antibody. In contrast, conjugates same antibody, modified degree either lysines or aspartic glutamic acid side chains, were heterogeneous their had...
The (6-maleimidocaproyl)hydrazone of doxorubicin was synthesized and conjugated to several mAbs, including chimeric BR96, via a Michael addition reaction thiol-containing mAbs. DTT reduction disulfides present in the mAb reliable general method for generating consistent number reactive SH groups. conjugates, after purification by Bio-Beads, were free unreacted linker and/or doxorubicin. All conjugates released under acidic conditions that mimic lysosomal environment, while they relatively...
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...
The synthesis of the highly potent and selective serotonin reuptake inhibitor 1 (BMS-594726) is described. In key construction step, an enantioselective alkylation indole nucleus with alpha-branched alpha,beta-unsaturated aldehyde 7 was accomplished utilizing MacMillan's imidazolidinone catalyst 3b. A rationale presented for unexpected stereochemical result, as well novel reactivity substrate. [reaction: see text]
Immunoconjugates of monoclonal antibody BR96 and Doxorubicin have been prepared using a novel series branched hydrazone linkers. Since each linker bound to the mAb carries two DOX molecules, DOX/mAb molar ratios these conjugates were approximately 16, twice that those previously with single-chain The stable at physiological pH 7, but released rapidly lysosomal 5. demonstrated antigen-specific cytotoxicity, more potent in vitro than conjugate on both (4-14-fold) (7-23-fold) basis. results...
The development of alpha7 nicotinic acetylcholine receptor agonists is considered a promising approach for the treatment cognitive symptoms in schizophrenia patients. In present studies we characterized novel agent, (2R)-N-(6-(1H-imidazol-1-yl)-4-pyrimidinyl)-4'H-spiro[4-azabicyclo[2.2.2]octane-2,5'-[1,3]oxazol]-2'-amine (BMS-933043), vitro and rodent models schizophrenia-like deficits cognition sensory processing. BMS-933043 showed potent binding affinity to native rat (Ki = 3.3 nM)...
Stability of antibody-drug conjugates (ADCs) in mouse serum is one the critical requirements for evaluation ADCs tumor models. Described herein a strategy to address instability uncialamycin linker-payloads through various chemical approaches that involve modification different parts linker and payload. This effort ultimately led identification m-amide p-aminobenzyl carbamate (MA-PABC) group resulted linkers with dramatic improvement stability without affecting desired proteolytic cleavage.
ADVERTISEMENT RETURN TO ISSUEPREVArticleNEXTInteractions of some novel amide-linked bis(acridines) with deoxyribonucleic acidH. Dalton King, W. David Wilson, and E. J. GabbayCite this: Biochemistry 1982, 21, 20, 4982–4989Publication Date (Print):September 28, 1982Publication History Published online1 May 2002Published inissue 28 September 1982https://doi.org/10.1021/bi00263a023RIGHTS & PERMISSIONSArticle Views114Altmetric-Citations32LEARN ABOUT THESE METRICSArticle Views are the...
The antidepressant activity of the N-methyl-D-aspartate (NMDA) receptor channel blocker, ketamine, has led to investigation negative allosteric modulators (NAMs) selective for NR2B subtype. clinical development NAMs would benefit from a translational pharmacodynamic biomarker that demonstrates brain penetration and functional inhibition receptors in preclinical species humans. Quantitative electroencephalography (qEEG) is measure can be used demonstrate effects across species. NMDA blockers,...
The design and synthesis of a series quinuclidine-containing spirooxazolidines ("spiroimidates") their utility as α7 nicotinic acetylcholine receptor partial agonists are described. Selected members the demonstrated excellent selectivity for over highly homologous 5-HT3A receptor. Modification N-spiroimidate heterocycle substituent led to (1S,2R,4S)-N-isoquinolin-3-yl)-4'H-4-azaspiro[bicyclo[2.2.2]octane-2,5'oxazol]-2'-amine (BMS-902483), potent agonist, which improved cognition in...
A series of 4-bicyclic heteroaryl 1,2,3,4-tetrahydroisoquinoline inhibitors the serotonin transporter (SERT), norepinephrine (NET), and dopamine (DAT) was discovered. The synthesis structure-activity relationship (SAR) these triple reuptake (TRIs) will be discussed. Compound 10i (AMR-2), a very potent inhibitor SERT, NET, DAT, showed efficacy in rat forced-swim mouse tail suspension models with minimum effective doses 0.3 1 mg/kg (po), respectively. At efficacious assays, exhibited...
(<i>R</i>)-3-((3S,4S)-3-fluoro-4-(4-hydroxyphenyl)piperidin-1-yl)-1-(4-methylbenzyl)pyrrolidin-2-one (BMS-986169) and the phosphate prodrug 4-((3<i>S</i>,4<i>S</i>)-3-fluoro-1-((R)-1-(4-methylbenzyl)-2-oxopyrrolidin-3-yl)piperidin-4-yl)phenyl dihydrogen (BMS-986163) were identified from a drug discovery effort focused on development of novel, intravenous glutamate <i>N</i>-methyl-d-aspartate 2B receptor (GluN2B) negative allosteric modulators (NAMs) for treatment-resistant depression (TRD)....
There is a significant unmet medical need for more efficacious and rapidly acting antidepressants. Toward this end, negative allosteric modulators of the N-methyl-d-aspartate receptor subtype GluN2B have demonstrated encouraging therapeutic potential. We report herein discovery preclinical profile water-soluble intravenous prodrug BMS-986163 (6) its active parent molecule BMS-986169 (5), which high binding affinity site (Ki = 4.0 nM) selective inhibition function (IC50 24 in cells. The...
The therapeutic treatment of negative symptoms and cognitive dysfunction associated with schizophrenia is a significant unmet medical need. Preclinical literature indicates that α7 neuronal nicotinic acetylcholine (nACh) receptor agonists may provide an effective approach to treating in schizophrenia. We report herein the discovery evaluation 1c (BMS-933043), novel potent nACh partial agonist high selectivity against other subtypes (>100-fold) 5-HT3A (>300-fold). In vivo activity was...
We describe the synthesis of quinuclidine-containing spiroimidates and their utility as α7 nicotinic acetylcholine receptor (nAChR) partial agonists. A convergent synthetic route allowed for rapid SAR investigation provided a diverse set fused 6,5-heteroaryl analogs. Two potent selective nAChR agonists, (1′S,3′R,4′S)-N-(7-bromopyrrolo[2,1-f][1,2,4]triazin-4-yl)-4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octan]-2-amine (20)...