A5047963982- Nicotinic Acetylcholine Receptors Study
- Crystallization and Solubility Studies
- X-ray Diffraction in Crystallography
- Receptor Mechanisms and Signaling
- Oxidative Organic Chemistry Reactions
- Synthetic Organic Chemistry Methods
- Synthesis and Biological Evaluation
- Pharmacological Receptor Mechanisms and Effects
- Catalytic C–H Functionalization Methods
- Chemical Synthesis and Analysis
- DNA and Nucleic Acid Chemistry
- Synthesis and pharmacology of benzodiazepine derivatives
- Cancer Treatment and Pharmacology
- Synthesis and Reactivity of Heterocycles
- Advanced biosensing and bioanalysis techniques
- Radical Photochemical Reactions
- Synthesis and Catalytic Reactions
- Asymmetric Synthesis and Catalysis
- HER2/EGFR in Cancer Research
- RNA and protein synthesis mechanisms
- Advanced Synthetic Organic Chemistry
- Protein Degradation and Inhibitors
- Synthesis of heterocyclic compounds
- RNA modifications and cancer
- Synthesis and Reactivity of Sulfur-Containing Compounds
Bristol-Myers Squibb (United States)
2013-2021
Baylor University
2017
Yale University
2001-2012
Heriot-Watt University
2001
Phosphorothioate nucleotides have emerged as powerful pharmacological substitutes of their native phosphodiester analogs with important translational applications in antisense oligonucleotide (ASO) therapeutics and cyclic dinucleotide (CDN) synthesis. Stereocontrolled installation this chiral motif has long been hampered by the systemic use phosphorus(III) [P(III)]-based reagent systems sole practical means assembly. A fundamentally different approach is described herein: invention a...
The promise of gene-based therapies is being realized at an accelerated pace, with more than 155 active clinical trials and multiple U.S. Food Drug Administration approvals for therapeutic oligonucleotides, by far most which contain modified phosphate linkages. These unnatural linkages have desirable biological physical properties but are often accessed difficulty using phosphoramidite chemistry. We report a flexible efficient [P(V)]–based platform that can install wide variety will into...
An operationally simple chemoselective transfer hydrogenation of alkenes using ruthenium metathesis catalysts is presented. Of great practicality, the reagents can be added directly to a reaction and effect product alkene in single pot at ambient temperature without need seal vessel prevent hydrogen gas escape. The reduction applicable range performed presence aryl halides benzyl groups, notable weakness Pd-catalyzed hydrogenations. Scope mechanistic considerations are
Assembly of the carbocyclic core CP-263,114 has been accomplished efficiently and in high yield. Key steps include a phenolic oxidation/intramolecular Diels−Alder sequence, tandem radical cyclization, late-stage fragmentation densely functionalized isotwistane skeleton.
A new annulation method for the preparation of imidazo[1,2-a]pyridine ring system under mild conditions is presented. Treatment a 2-aminopyridine with dimethylketal tosylate in acetonitrile at elevated temperature (80–140 °C) presence catalytic Sc(OTf)3 provides product good yield. The broadly applicable to electron-poor 2-aminopyridines and displays complementary profile classic by reaction bromoketone electron-rich -neutral substrates. scope process mechanistic considerations are discussed.
Abstract Described herein is a synthetic strategy for the total synthesis of (±)‐phomoidride D. This highly efficient and stereoselective approach provides rapid assembly carbocyclic core by way tandem phenolic oxidation/intramolecular Diels–Alder cycloaddition. A subsequent SmI 2 ‐mediated cyclization cascade delivers an isotwistane intermediate poised Wharton fragmentation that unveils requisite bicyclo[4.3.1]decene skeleton sets stage completion.
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...
An efficient and highly stereoselective approach toward the phomoidride family of natural products is described. The carbocyclic core structure was assembled using a tandem phenolic oxidation/Diels-Alder cycloaddition 5-exo-trig/5-exo-trig radical cyclization to deliver an isotwistane intermediate that, upon late-stage xanthate-initiated Grob fragmentation, furnishes requisite bicyclo[4.3.1]decene.
A series of tetrahydroisoquinoline-based benzodiazepine dimers were synthesized and tested for in vitro cytotoxicity against a panel cancer cell lines. Structure–activity relationship investigation various spacers guided by molecular modeling studies helped to identify compounds with picomolar activity. Payload 17 was conjugated anti-mesothelin anti-fucosylated monosialotetrahexosylganglioside (FucGM1) antibodies using lysosome-cleavable valine–citrulline dipeptide linkers via heterogeneous...
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)...
Hundreds of dominant-negative myosin mutations have been identified that lead to hypertrophic cardiomyopathy, and the biomechanical link between mutation disease is heterogeneous across this patient population. To increase therapeutic feasibility treating diverse genetic population, we investigated ability locked nucleic acid (LNA)-modified antisense oligonucleotides (ASOs) selectively knock down mutant transcripts by targeting single-nucleotide polymorphisms (SNPs) were found be common in...
Treatment of the azabicyclo[2.2.1]heptene derivative 4 with mCPBA for 3–5 seconds generates oxazabicyclo[3.2.1]octene 7 (X-ray structure) via rapid Meisenheimer rearrangement N-oxide 5, whilst heating in MeCN 4–6 h leads to further more thermodynamically stable oxazabicyclo[3.3.0]octene isomer 6; 6 and can be readily reduced enantio-pure hydroxylated cyclopentylglycine derivatives.
An optimized large-scale synthesis of (2S,3aR,7aS)-tert-butyl hexahydro-2,5-methanopyrrolo[3,2-c]pyridine-1(4H)-carboxylate (1A), an important intermediate for nicotinic acetylcholine receptor agonists, is described. The key feature the involves three transformations in a one-pot process, including debenzylation and ring hydrogenation two fused bicyclic rings. Multihundred gram quantities 1A were prepared.