A5050991722- Cyclopropane Reaction Mechanisms
- Computational Drug Discovery Methods
- Analytical Chemistry and Chromatography
- Drug Solubulity and Delivery Systems
- N-Heterocyclic Carbenes in Organic and Inorganic Chemistry
- Analytical Methods in Pharmaceuticals
- Free Radicals and Antioxidants
- Synthetic Organic Chemistry Methods
- Chemical Reactions and Mechanisms
- Cancer therapeutics and mechanisms
- Protein Degradation and Inhibitors
- RNA Interference and Gene Delivery
- Insect and Pesticide Research
- Cancer Mechanisms and Therapy
- Advanced Drug Delivery Systems
- Crystallization and Solubility Studies
- Organometallic Complex Synthesis and Catalysis
- Spectroscopy and Quantum Chemical Studies
- Antibiotics Pharmacokinetics and Efficacy
- Lung Cancer Treatments and Mutations
- Electron Spin Resonance Studies
- Phytochemical compounds biological activities
- Protein purification and stability
- Cyclone Separators and Fluid Dynamics
- Granular flow and fluidized beds
Amgen (United States)
2013-2025
McMaster University
2000-2005
University of Calgary
2002-2004
Pfizer (United States)
2004
Ab initio calculations at the B3LYP/6-31G(d) level and scaled particle theory, combined with entropies of activation derived from experimental Arrhenius A factors, were applied to examine origin loss gaseous-phase entropy a substance upon solution. Eight reactions in water analyzed: H atom reacting methanol, ethanol, 2-propanol, methanediol ethylene glycol; methanethiol radicals, methyl, hydroxymethyl, 2-hydroxy-2-propyl. The results suggest that observed is entirely due changes solvent....
Zeneth, a software application for the prediction of chemical degradation small organic molecules, incorporates knowledge base rules to predict pathways. In addition, contains property predictors that modulate predicted likelihood given product. this study, C–H bond dissociation energy (C–H BDE) predictor, which has been integrated into software, was utilized. To determine software's predictive capabilities [using its (2020.1.0 KB)], experimentally derived profiles 25 drug substances were...
Zeneth is a new software application capable of predicting degradation products derived from small molecule active pharmaceutical ingredients. This study was aimed at understanding the current status Zeneth's predictive capabilities and assessing gaps in predictivity. Using data 27 drug substances five companies, evolution predictions through knowledge base development since 2009 evaluated. The experimentally observed forced degradation, accelerated, long-term stability studies were compared...
In the previous report, we described discovery and optimization of novel small molecule disruptors GK-GKRP interaction culminating in identification 1 (AMG-1694). Although this analogue possessed excellent vitro potency was a useful tool compound initial proof-of-concept experiments, high metabolic turnover limited its advancement. Guided by combination metabolite structure-based design, have successfully discovered potent metabolically stable disruptor (27, AMG-3969). When administered to...
In nonsmall cell lung cancer (NSCLC), the threonine(790)-methionine(790) (T790M) point mutation of EGFR kinase is one leading causes acquired resistance to first generation tyrosine inhibitors (TKIs), such as gefitinib and erlotinib. Herein, we describe optimization a series 7-oxopyrido[2,3-d]pyrimidinyl-derived irreversible kinase. This led discovery compound 24 which potently inhibits gefitinib-resistant EGFR(L858R,T790M) with 100-fold selectivity over wild-type EGFR. Compound displays...
The Arrhenius parameters and rates of reaction three hydroxyradicals, methyl radical, the hindered primary C-centred radical from t-butyl alcohol with dithiothreitol were measured by pulse radiolysis in water. bimolecular rate constants found to be order: ˙C(CH3)2OH > ˙CH(CH3)OH ˙CH2OH ˙CH3 ˙CH2C(CH3)2OH. these, ˙C(CH3)2OH, ˙CH2OH, ˙CH3, methanethiol examined at ab initio B3LYP/6311+G(d,p) level, coupled transition state theory, both gas phase solution. solvent effects are evaluated two...
The reactions of methanethiyl radicals (CH3S˙) with the cyclic anhydrides glycine (1a), alanine (L,L-1b and D,L-1b), sarcosine (1c), acyclic peptides, N-formylglycinamide (3a) N-formylalaninamide (3b), were studied by means theoretical calculations at B3LYP/6-311+G(d,p) level theory. Free energies in gas phase determined classical harmonic oscillator-rigid rotator model, used to estimate rates H-transfer αC-site peptides. effects aqueous solution estimated SCIPCM procedure combination...
Recent work has shown that dioxycarbenes can readily undergo homolytic fragmentations to radicals in solution. Previous workers have found some theoretical evidence for a transition state the homolysis of dihydroxycarbene HOCO and H using CISD method, but they were not able conclude whether such barrier was real or an artifact approximation. In this hydroxycarbene is examined at CAS MRCI levels theory cc-pVDZ basis set. The atomic molecular properties are atoms molecules. At highest level...
Compounds 1 (N1-(3-ethynylphenyl)-6-methyl-N5-(3-(6-(methylamino)pyrimidin-4-yl)pyridin-2-yl) isoquinoline-1,5-diamine) and 2 (N-(3-ethynylphenyl)-6,7-bis(2-methoxyethoxy)quinazolin-4-amine; Erlotinib/Tarceva) are kinase inhibitors that contain a terminal phenyl acetylene moiety. When incubated in the presence of P450 NADPH, anticipated acetic acid metabolite was formed. 10 mM N-acetyl-l-cysteine added to incubation mixtures, product reduced at 25 or higher concentration NAC, formation...
Using the pulse radiolysis and other radiation chemical techniques, reaction kinetics of ˙CH3 ˙CH2OH radicals with alanine anhydride, glycine anhydride sarcosine were examined in aqueous solution. The second order rate constant has been determined at 2 × 105 dm3 mol−1 s−1. A very similar value (8 104 s−1) obtained by measuring methane ethane yields as a function concentration different dose rates evaluation these data computer analysis. Similar experiments carried out yielded identical...
Warkentin and Venneri have shown that the bulk of rearrangement products allyloxy(methoxy)carbenes result from a homolysis–recoupling mechanism in contrast to known cases [2,3]sigmatropic rearrangements analogous (bisheteroatom)carbenes (J. Am. Chem. Soc., 1998, 120, 11182). Herein, allyloxy(hydroxy)carbene is used as model investigate fragmentations with density functional Møller–Plesset calculations. [1,2]Migration, rearrangement, β-scission triplet, homolysis singlet state are all...
Abstract Unlike electrophilic carbenes, which react at sulfur to produce thiocarbonyl ylide intermediates, dimethoxycarbene (DMC), generated by thermolysis of an oxadiazoline 110°C in benzene a sealed tube, reacts carbon, possibly generate zwitterionic intermediate, or both carbon and concerted process that generates thiirane. In case the strained 2,2,4,4‐tetramethylcyclobutane‐1,3‐dithione ( 2 ), assumed zwitterion undergoes ring expansion. analogous reactions, unstrained thiones afford...