A5021010428- Phosphodiesterase function and regulation
- Cholinesterase and Neurodegenerative Diseases
- Receptor Mechanisms and Signaling
- Chemistry and Chemical Engineering
- Chemical Synthesis and Analysis
- Catalytic C–H Functionalization Methods
- Asymmetric Synthesis and Catalysis
- HIV/AIDS drug development and treatment
- Asymmetric Hydrogenation and Catalysis
- Biochemical and Molecular Research
- Chemical synthesis and alkaloids
- Cytomegalovirus and herpesvirus research
- Axial and Atropisomeric Chirality Synthesis
- Catalytic Cross-Coupling Reactions
- Porphyrin and Phthalocyanine Chemistry
- Computational Drug Discovery Methods
- Synthesis and Catalytic Reactions
- Pharmaceutical Economics and Policy
- HIV Research and Treatment
- Viral-associated cancers and disorders
- Herpesvirus Infections and Treatments
- Science, Research, and Medicine
- Photochemistry and Electron Transfer Studies
- Multicomponent Synthesis of Heterocycles
- Molecular Sensors and Ion Detection
United States Military Academy
2011-2024
Merck & Co., Inc., Rahway, NJ, USA (United States)
2012-2024
Amgen (United States)
2014
Harvard University
2003-2008
Carnegie Mellon University
2001-2003
Highly enantioenriched indolizinone and quinolizinone products are obtained in the thiourea-catalyzed cyclization of tryptamine-derived hydroxylactams. Substituent counterion effect studies point to a novel mechanism catalysis involving rate-limiting anion abstraction binding by thiourea.
Abstract We report the discovery of asymmetric aza‐Baylis–Hillman (ABH) reactions N‐p‐ nitrobenzenesulfonylimines with methyl acrylate catalyzed by chiral thiourea derivatives. A series aromatic imines was found to undergo coupling unprecedented levels enantioselectivity (87–99% ee), albeit only in modest (25–49%) yields. DABCO‐acrylate‐imine adduct isolated as a key intermediate ABH reaction. provide mechanistic analysis based on identity this well kinetic investigations and isotope...
The regio- and enantioselective cyclization of pyrroles onto N-acyliminium ions generated in situ from hydroxylactams is reported. Modest to excellent ee's yields are obtained these novel Pictet−Spengler-type reactions with a chiral thiourea-pyrrole catalyst. Useful synthetic transformations the versatile pyrroloindolizidinone pyrroloquinolizidinone products presented.
The catalytic, asymmetric syntheses of quinine and quinidine were achieved in 16 steps. recently developed salen(Al)-catalyzed enantioselective Michael addition methyl cyanoacetate served to set the crucial C4 stereocenter 92% ee, a late-stage dihydroxylation was used differentiate common intermediate access two desired diastereomeric products with high selectivity.
A robust and general catalyst system facilitates the alkoxylation of activated heteroaryl halides with primary, secondary, select tertiary alcohols without need for an excess either coupling partner (see scheme). This displays broad functional-group tolerance excellent regioselectivity, is insensitive to order reagent addition. Detailed facts importance specialist readers are published as "Supporting Information". Such documents peer-reviewed, but not copy-edited or typeset. They made...
PDE10A is an important regulator of striatal signaling that, when inhibited, can normalize dysfunctional activity. Given the involvement activity with schizophrenia, inhibition represents a potentially novel means for its treatment. With goal developing inhibitors, early optimization fragment hit through rational design led to series potent pyrimidine inhibitors that required further improvements in physicochemical properties, off-target activities, and pharmacokinetics. Herein we describe...
This perspective details practical techniques for reducing the waste generated from chromatography within pharmaceutical drug discovery labs and additionally provides sustainable alternatives to flash chromatography.
A series of studies is presented to characterize the photophysical properties a novel type aggregate formed by spontaneous noncovalent assembly numerous cofacial dimers cyanine dyes (DiSC3+(5)) minor groove poly(dI−dC) DNA. The dimensions these helical aggregates, first synthesized and characterized Armitage co-workers (J. Am. Chem. Soc. 2000, 122, 9977−9986), are restricted width dye dimer because steric constraints in groove, though length can extend essentially for full DNA template....
Phosphodiesterase 10A (PDE10A) is a novel therapeutic target for the treatment of schizophrenia. Here we report role PDE10A in regulation caloric intake and energy homeostasis. PDE10A-deficient mice are resistant to diet-induced obesity (DIO) associated metabolic disturbances. Inhibition weight gain due hypophagia after fed highly palatable diet rich fats sugar but not standard diet. deficiency produces decrease without affecting meal frequency, daytime versus nighttime feeding behavior, or...
Efforts to develop an HIV-1 vaccine include those focusing on conserved structural elements as the target of broadly neutralizing monoclonal antibodies. MAb D5 binds a highly hydrophobic pocket gp41 N-heptad repeat (NHR) coiled coil and neutralizes through prevention viral fusion entry. Assessment 17-mer 36-mer NHR peptides presenting epitope in rodent immunogenicity studies showed that longer peptide elicited higher titers antibodies, suggesting epitopes outside may exist. Although...
The search for new molecular constructs that resemble the critical two-metal binding pharmacophore required HIV integrase strand transfer inhibition represents a vibrant area of research within drug discovery. Here we present discovery class inhibitors based on 2-pyridinone core MK-0536. These efforts led to identification two lead compounds with excellent antiviral activity and preclinical pharmacokinetic profiles support once-daily human dose prediction. Dose escalating PK studies in dog...
Process safety is an important consideration not only when conducting reactions on manufacturing scale, but also lab and kilo scale. This contribution presents a discussion of Merck's Reaction Review policy, originally specific to Chemistry now applied broadly across the whole chemistry organization. Details policy case studies are included.
Abstract All herpesviruses encode a conserved DNA polymerase that is required for viral genome replication and serves as an important therapeutic target. Currently available herpesvirus therapies include nucleoside non-nucleoside inhibitors (NNI) target the DNA-bound state of block replication. Here we report ternary complex crystal structure Herpes Simplex Virus 1 bound to 4-oxo-dihydroquinoline NNI, PNU-183792 (PNU), at 3.5 Å resolution. PNU active site, displacing template strand inducing...
Acinetobacter baumannii, a commonly multidrug-resistant Gram-negative bacterium responsible for large numbers of bloodstream and lung infections worldwide, is increasingly difficult to treat constitutes growing threat human health. Structurally novel antibacterial chemical matter that can evade existing resistance mechanisms essential addressing this critical medical need. Herein, we describe our efforts inhibit the A. baumannii lipooligosaccharide (LOS) ATP-binding cassette (ABC)...
Robust und allgemein anwendbar ist ein Katalysatorsystem für die Alkoxylierung aktivierter halogenierter Heteroarene mit primären, sekundären ausgewählten tertiären Alkoholen, bei der keiner Kupplungspartner im Überschuss eingesetzt werden muss (siehe Schema). Das verträglich vielen funktionellen Gruppen, wirkt überaus regioselektiv stellt keine Anforderungen an Reihenfolge Reagentienzugabe. Detailed facts of importance to specialist readers are published as ”Supporting Information”. Such...
Stark spectroscopy (electroabsorption) is used to study the variation of electronic properties with size helical H-aggregates that are formed by spontaneous noncovalent assembly co-facial dimers cyanine dye (DiSC2(5)) into minor groove double-helical DNA. The unique and important property these aggregates, first synthesized characterized Armitage co-workers (J. Am. Chem. Soc. 1999, 121, 2987), their controlled DNA template. Specifically, length aggregate determined template its width along π...
MK-8189 is a novel phosphodiesterase 10A (PDE10A) inhibitor being evaluated in clinical studies for the treatment of schizophrenia. PDE10A cyclic nucleotide enzyme highly expressed medium spiny neurons striatum. exhibits subnanomolar potency on and has excellent pharmaceutical properties. Oral administration significantly increased guanosine monophosphate phospho glutamate receptor 1 rat striatal tissues. Activation dopamine D1 direct D2 indirect pathways was demonstrated by detecting...