A5047723972- Asymmetric Synthesis and Catalysis
- Crystallization and Solubility Studies
- X-ray Diffraction in Crystallography
- Organic Chemistry Cycloaddition Reactions
- Synthetic Organic Chemistry Methods
- Computational Drug Discovery Methods
- Chemical Synthesis and Analysis
- Drug Transport and Resistance Mechanisms
- Alzheimer's disease research and treatments
- Cyclopropane Reaction Mechanisms
- Synthesis and Biological Evaluation
- Neuroscience and Neuropharmacology Research
- Asymmetric Hydrogenation and Catalysis
- Chemical Reaction Mechanisms
- Oxidative Organic Chemistry Reactions
- Fluorine in Organic Chemistry
- Cholinesterase and Neurodegenerative Diseases
- Marine Sponges and Natural Products
- Treatment of Major Depression
- Chemical Synthesis and Reactions
- Receptor Mechanisms and Signaling
- Chemical synthesis and alkaloids
- Neurotransmitter Receptor Influence on Behavior
- Tryptophan and brain disorders
- Axial and Atropisomeric Chirality Synthesis
Biohaven Pharmaceuticals (United States)
2024
Bristol-Myers Squibb (United States)
2003-2019
Bristol-Myers Squibb (Germany)
2005-2017
University of Illinois Urbana-Champaign
1993-2007
Harvard University
1998-1999
Urbana University
1995-1997
Pennsylvania State University
1989-1990
During the course of our research efforts to develop a potent and selective γ-secretase inhibitor for treatment Alzheimer's disease, we investigated series carboxamide-substituted sulfonamides. Optimization based on potency, Notch/amyloid-β precursor protein selectivity, brain efficacy after oral dosing led discovery 4 (BMS-708163). Compound is (Aβ40 IC50 = 0.30 nM), demonstrating 193-fold selectivity against Notch. Oral administration significantly reduced Aβ40 levels sustained periods in...
An efficient, total synthesis of the Sceletium alkaloid (−)-mesembrine is accomplished in seven steps and 19% yield from a functionalized nitroalkene (itself prepared six 34% ethyl 3-bromopropionate). The construction octahydroindole framework mesembrine features tandem inter [4 + 2]/intra [3 2] cycloaddition 2,2-disubstituted 1-nitroalkene chiral vinyl ether derived (1R,2S)-2-(1-methyl-1-phenylethyl)cyclohexanol as central strategic element. two stereogenic centers natural product, which...
ADVERTISEMENT RETURN TO ISSUEPREVCommunicationNEXTTotal Synthesis of (±)-Batrachotoxinin AMichio Kurosu, Lawrence R. Marcin, Timothy J. Grinsteiner, and Yoshito KishiView Author Information Department Chemistry Chemical Biology Harvard University, Cambridge, Massachusetts 02138 Cite this: Am. Chem. Soc. 1998, 120, 26, 6627–6628Publication Date (Web):June 18, 1998Publication History Received14 April 1998Published online18 June inissue 1 July...
ADVERTISEMENT RETURN TO ISSUEPREVArticleNEXTAsymmetric Nitroalkene [4 + 2] Cycloadditions: Enantioselective Synthesis of 3-Substituted and 3,4-Disubstituted PyrrolidinesScott E. Denmark Lawrence R. MarcinCite this: J. Org. Chem. 1995, 60, 10, 3221–3235Publication Date (Print):May 1, 1995Publication History Published online1 May 2002Published inissue 1 1995https://pubs.acs.org/doi/10.1021/jo00115a043https://doi.org/10.1021/jo00115a043research-articleACS PublicationsRequest reuse...
ADVERTISEMENT RETURN TO ISSUEPREVArticleNEXTA general method for the preparation of 2,2-disubstituted 1-nitroalkenesScott E. Denmark and Lawrence R. MarcinCite this: J. Org. Chem. 1993, 58, 15, 3850–3856Publication Date (Print):July 1, 1993Publication History Published online1 May 2002Published inissue 1 July 1993https://doi.org/10.1021/jo00067a016RIGHTS & PERMISSIONSArticle Views1298Altmetric-Citations61LEARN ABOUT THESE METRICSArticle Views are COUNTER-compliant sum full text article...
ADVERTISEMENT RETURN TO ISSUEPREVArticleNEXTNitroalkene Inter [4 + 2]/Intra [3 2] Tandem Cycloadditions. 7. Application of (R)-(-)-2,2-Diphenylcyclopentanol as the Chiral AuxiliaryScott E. Denmark, Mark Schnute, Lawrence R. Marcin, and Atli ThorarensenCite this: J. Org. Chem. 1995, 60, 10, 3205–3220Publication Date (Print):May 1, 1995Publication History Published online1 May 2002Published inissue 1...
ADVERTISEMENT RETURN TO ISSUEPREVArticleNEXTNitroalkene [4+2] cycloaddition as a general and stereoselective route to the synthesis of 3,3- 3,4-disubstituted pyrrolidinesScott E. Denmark Lawrence R. MarcinCite this: J. Org. Chem. 1993, 58, 15, 3857–3868Publication Date (Print):July 1, 1993Publication History Published online1 May 2002Published inissue 1 July 1993https://pubs.acs.org/doi/10.1021/jo00067a017https://doi.org/10.1021/jo00067a017research-articleACS PublicationsRequest reuse...
Alzheimer's disease (AD) is a progressive neurodegenerative disease. Amyloid beta (Abeta) peptides are hypothesized to cause the initiation and progression of AD based on pathologic data from patients, genetic analysis mutations that early onset forms AD, preclinical studies. Based this hypothesis, beta-site amyloid precursor protein (APP)-cleaving enzyme 1 (BACE1) inhibitors an attractive therapeutic approach for because cleavage APP by BACE1 required form Abeta. In study, three potent...
A triazine hit identified from a screen of the BMS compound collection was optimized for potency, in vivo activity, and off-target profile to produce bicyclic pyrimidine γ-secretase modulator BMS-932481. The showed robust reductions Aβ1-42 Aβ1-40 plasma, brain, cerebrospinal fluid mice rats. Consistent with mechanism, increases Aβ1-37 Aβ1-38 were observed, no change total amount Aβ1-x produced. No Notch-based toxicity overall preclinical BMS-932481 supported its further evaluation human...
[reaction: see text] Substituted 1-tosyl-3-vinylindoles undergo catalytic asymmetric cyclopropanation with ethyl- and tert-butyldiazoacetate to afford N-protected trans-2-(indol-3-yl)-1-cyclopropanecarboxylic esters in good yield high enantiomeric excess (81-88% ee). The resulting cycloadducts are demonstrated be useful intermediates for the synthesis of conformationally restricted, homotryptamine-like analogues such as BMS-505130.
A series of indole cyclopropylmethylamines were found to be potent serotonin reuptake inhibitors. Nitrile substituents at the 5 and 7 positions ring gave high affinity for hSERT, preferred cyclopropane stereochemistry was determined (1S,2S)-trans. The cis-cyclopropanes had 20- 30-fold less than trans, cis (1R,2S)-cis. Substitution N-1 position with methyl or ethyl groups a 10- decrease in suggesting either hydrogen-bonding interaction limited steric tolerance region nitrogen. Compound...
(<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...
Alzheimer’s disease is the most prevalent cause of dementia and associated with accumulation amyloid- β peptide (A ), particularly 42-amino acid A 1-42, in brain. 1-42 levels can be decreased by γ -secretase modulators (GSM), which are small molecules that modulate -secretase, an enzyme essential for production. BMS-869780 a potent GSM 1-40 increased 1-37 1-38, without inhibiting overall peptides or other APP processing intermediates. also did not inhibit Notch lowered brain evidence...
Truncation of the S3 substituent biaryl aminothiazine 2, a potent BACE1 inhibitor, led to low molecular weight 5 with moderate activity. Despite its activity, compound demonstrated significant brain Aβ reduction in rodents. The metabolic instability was overcome by replacement 6-dimethylisoxazole, soft spot, pyrimidine ring. Thus, truncation represents viable approach discovery orally bioavailable, brain-penetrant inhibitors.
Assess in vitro activity and vivo efficacy safety of BHV-2100.