A5045988901- Fluorine in Organic Chemistry
- Nitric Oxide and Endothelin Effects
- Alzheimer's disease research and treatments
- Computational Drug Discovery Methods
- Cancer-related Molecular Pathways
- Advanced Chemical Physics Studies
- Metabolism, Diabetes, and Cancer
- Asymmetric Hydrogenation and Catalysis
- Synthesis and Reactions of Organic Compounds
- Pancreatic function and diabetes
- Electron Spin Resonance Studies
- Organic Chemistry Cycloaddition Reactions
- Chemical Synthesis and Analysis
- Asymmetric Synthesis and Catalysis
- Chemical Reaction Mechanisms
- X-ray Diffraction in Crystallography
- Crystallization and Solubility Studies
- Synthesis and Characterization of Heterocyclic Compounds
- Radical Photochemical Reactions
- Cholinesterase and Neurodegenerative Diseases
- Synthesis and Reactivity of Heterocycles
- Crystallography and molecular interactions
- Advanced Synthetic Organic Chemistry
- Oxidative Organic Chemistry Reactions
- Drug Transport and Resistance Mechanisms
Fate Therapeutics (United States)
2024
Amgen (United States)
2011-2020
Pasadena City College
2020
California Institute of Technology
2019
Duke University
2009
University of Florida
1996-2006
University of California, Los Angeles
1998-2005
The University of Tokyo
2005
Instituto Politécnico Nacional
2004
Kodak (United States)
1999-2003
Electron deficient, bivalent sulfur atoms have two areas of positive electrostatic potential, a consequence the low-lying σ* orbitals C–S bond that are available for interaction with electron donors including oxygen and nitrogen and, possibly, π-systems. Intramolecular interactions by far most common manifestation this effect, which offers means modulating conformational preferences molecule. Although well-documented phenomenon, priori applications in drug design relatively sparse...
The basis for unprecedented noncovalent bonding between anions and the aryl centroid of electron-deficient aromatic rings has been demonstrated by an ab initio study interaction 1,3,5-triazine fluoride, chloride, azide ion at MP2 level theory. Minima are also located corresponding to C[bond]H...X(-) hydrogen bonding, reactive complexes nucleophilic attack on triazine ring, pi-stacking interactions (with azide). Trifluoro-1,3,5-triazine participates in complexation forms with anions. This...
KRASG12C has emerged as a promising target in the treatment of solid tumors. Covalent inhibitors targeting mutant cysteine-12 residue have been shown to disrupt signaling by this long-“undruggable” target; however clinically viable yet be identified. Here, we report efforts exploit cryptic pocket (H95/Y96/Q99) identified identify suitable for clinical development. Structure-based design leading identification novel quinazolinone scaffold are described, along with optimization that overcame...
We recently reported the discovery of AM-8553 (1), a potent and selective piperidinone inhibitor MDM2-p53 interaction. Continued research investigation N-alkyl substituent this series, focused in particular on previously underutilized interaction shallow cleft MDM2 surface, led to one-carbon tethered sulfone which gave rise substantial improvements biochemical cellular potency. Further produced AMG 232 (2), is currently being evaluated human clinical trials for treatment cancer. Compound 2...
A potential of about −0.8 (±0.2) V (at 1 M versus normal hydrogen electrode) for the reduction nitric oxide (NO) to its one-electron reduced species, nitroxyl anion ( 3 NO − ) has been determined by a combination quantum mechanical calculations, cyclic voltammetry measurements, and chemical experiments. This value is in accord with some, but not most commonly accepted, previous electrochemical measurements involving NO. Reduction highly unfavorable, predicted −1.7 at electrode. These results...
Experimental and theoretical data are provided for a set of 11 pericyclic reactions unsaturated hydrocarbons. Literature experimental evaluated standardized to ΔH⧧0K comparison theory. Hartree−Fock, MP2, CASSCF, CASPT2, density functional theory (B3LYP, BPW91, MPW1K, KMLYP functionals), CBS-QB3 transition-structure geometries, activation enthalpies entropies, reaction entropies these reported compared results. For enthalpies, several functionals rival CASPT2 closest agreement with...
The redox siblings nitroxyl (HNO) and nitric oxide (NO) have often been assumed to undergo casual reactions in biological systems. However, several recent studies demonstrated distinct pharmacological effects for donors of these two species. Here, infusion the HNO donor Angeli's salt into normal dogs resulted elevated plasma levels calcitonin gene-related peptide, whereas neither NO diethylamine/NONOate nor nitrovasodilator nitroglycerin had an appreciable effect on basal levels. Conversely,...
A "molecular surgery" approach has been used to create an opening within a fullerene cage that is large enough allow atoms and small molecules pass through. The thermodynamics for the insertion of He H2 into open (left right pictures, respectively) as well their escape have studied by NMR spectroscopy theoretical methods.
Ab initio calculations at the MP2/6-311++G** level on model systems (N-methylpyridinium complexes of dimethyl ether and phosphate anion) provide quantitative measures large stabilization energies that arise from [C-H...O] contacts in charged systems. These attractive interactions control (i) self-assembly bipyridinium-based catenanes rotaxanes solution, (ii) self-organization left-handed Z-DNA with alternating [dC-dG] sequences solid state, (iii) binding pyridinium derivatives single-...
Structure-based rational design led to the discovery of novel inhibitors MDM2–p53 protein–protein interaction. The affinity these compounds for MDM2 was improved through conformational control both piperidinone ring and appended N-alkyl substituent. Optimization afforded 29 (AM-8553), a potent selective inhibitor with excellent pharmacokinetic properties in vivo efficacy.
Tumor protein 53 (p53) is a critical regulator of cell cycle and apoptosis that frequently disabled in human tumors. In many tumor types, p53 deleted or mutated, but others inactivated by overexpression amplification its negative mouse double minute 2 (MDM2). A high-throughput screening effort identified 6,7-bis(4-bromophenyl)-7,12-dihydro-6H-chromeno[4,3-d][1,2,4]triazolo[1,5-a]pyrimidine as potent inhibitor the MDM2−p53 protein−protein interaction. This hit was found to be chemically...
Success in the design of targeted covalent inhibitors depends part on a knowledge factors influencing electrophile reactivity. In an effort to further develop understanding structure–reactivity relationships among N-arylacrylamides, we determined glutathione (GSH) reaction rates for family N-arylacrylamides independently substituted at ortho-, meta-, and para-positions with 11 different groups common inhibitor design. We find that substituent effects show linear Hammett correlation...
Using fragment-based screening of a focused fragment library, 2-aminoquinoline 1 was identified as an initial hit for BACE1. Further SAR development supported by X-ray structures BACE1 cocrystallized with various ligands and molecular modeling studies to expedite the discovery potent compounds. These strategies enabled us integrate C-3 side chain on extending deep into P2′ binding pocket enhancing ligand's potency. We were able improve potency subnanomolar range, over 106-fold more than (900...
KRAS regulates many cellular processes including proliferation, survival, and differentiation. Point mutants of have long been known to be molecular drivers cancer. p.G12C, which occurs in approximately 14% lung adenocarcinomas, 3-5% colorectal cancers, low levels other solid tumors, represents an attractive therapeutic target for covalent inhibitors. Herein, we disclose the discovery a class novel, potent, selective inhibitors KRASG12C identified through custom library synthesis screening...
The gas phase and aqueous thermochemistry reactivity of nitroxyl (nitrosyl hydride, HNO) were elucidated with multiconfigurational self-consistent field hybrid density functional theory calculations continuum solvation methods. pK a HNO is predicted to be 7.2 ± 1.0, considerably different from the value 4.7 reported pulse radiolysis experiments. ground-state triplet nature NO − affects rates acid-base chemistry HNO/NO couple. highly reactive toward dimerization addition soft nucleophiles but...
ADVERTISEMENT RETURN TO ISSUEPREVCommunicationNEXTS−N Dissociation Energies of S-Nitrosothiols: On the Origins Nitrosothiol Decomposition RatesMichael D. Bartberger, Joseph Mannion, Steven C. Powell, Jonathan S. Stamler, K. N. Houk, and Eric J. TooneView Author Information Department Chemistry Biochemistry University California, Los Angeles, California 90095 Chemistry, Duke Durham, North Carolina 27708 Howard Hughes Medical Institute Departments Medicine Center, Cite this: Am. Chem. Soc....
We previously reported the discovery of AMG 232, a highly potent and selective piperidinone inhibitor MDM2–p53 interaction. Our continued search for diverse analogues led to novel morpholinone MDM2 inhibitors. This change core has significant impact on both potency metabolic stability compared series. Within this series, AM-8735 emerged as an with remarkable biochemical (HTRF IC50 = 0.4 nM) cellular (SJSA-1 EdU 25 nM), well pharmacokinetic properties. Compound 4 also shows excellent...
Structural analysis of both the MDM2-p53 protein-protein interaction and several small molecules bound to MDM2 led design synthesis tetrasubstituted morpholinone 10, an inhibitor with a biochemical IC50 1.0 μM. The cocrystal structure 10 inspired two independent optimization strategies resulted in discovery morpholinones 16 27 possessing distinct binding modes. Both analogues were potent inhibitors cellular assays, (IC50 = 0.10 μM) also displayed suitable PK profile for vivo animal...
GPR40 (FFAR1 or FFA1) is a target of high interest being pursued to treat type II diabetes due its unique mechanism leading little risk hypoglycemia. We recently reported the discovery AM-1638 (2), potent full agonist GPR40. In this report, we present agonists containing conformationally constrained tricyclic spirocycles and their structure-activity relationships more such as AM-5262 (26) with improved rat PK profile general selectivity profile. enhanced glucose stimulated insulin secretion...
We have studied the behavior of isomers and analogues by traveling wave ion mobility mass spectrometry (TWIM-MS) using drift-gases with varying masses polarizabilities. Despite reduced length cell (18 cm), a pair constitutional isomers, N-butylaniline para-butylaniline, theoretical collision cross-section values in helium (ΩHe ) differing as little 1.2 Å(2) (1.5%) but possessing contrasting charge distribution, showed baseline peak-to-peak resolution (Rp-p for their protonated molecules,...
Fragment-based drug discovery (FBDD) has become a widely used tool in small-molecule efforts. One of the most commonly biophysical methods detecting weak binding fragments is nuclear magnetic resonance (NMR) spectroscopy. In particular, FBDD performed with 19F NMR-based been shown to provide several advantages over 1H NMR using traditional magnetization-transfer and/or two-dimensional methods. Here, we demonstrate utility and power 19F-based fragment screening by detailing identification...
A comprehensive understanding of structure–reactivity relationships is critical to the design and optimization cysteine-targeted covalent inhibitors. Herein, we report glutathione (GSH) reaction rates for N-phenyl acrylamides with varied substitutions at α- β-positions acrylamide moiety. We find that GSH can generally be understood in terms electron donating or withdrawing ability substituent. When installed β-position, aminomethyl substituents amine pKa's > 7 accelerate, while those < slow...
An enantioselective iridium-catalyzed allylic alkylation of malonates with trisubstituted electrophiles to form all-carbon quaternary stereocenters is reported. This reaction proceeds at ambient temperature and enables the preparation a wide range enantioenriched products in up 93% yield 97% ee. The can be readily converted several valuable building blocks such as vicinal β-quaternary acids.