A5073887610- Synthetic Organic Chemistry Methods
- Asymmetric Synthesis and Catalysis
- X-ray Diffraction in Crystallography
- Crystallization and Solubility Studies
- Natural Compound Pharmacology Studies
- Chemical Synthesis and Analysis
- Biological and pharmacological studies of plants
- Lipid metabolism and biosynthesis
- Catalytic C–H Functionalization Methods
- Receptor Mechanisms and Signaling
- Asymmetric Hydrogenation and Catalysis
- Synthesis of Organic Compounds
- Oxidative Organic Chemistry Reactions
- Endoplasmic Reticulum Stress and Disease
- Diverse Scientific Research Studies
- Neuroscience and Neuropharmacology Research
- Catalytic Cross-Coupling Reactions
- SARS-CoV-2 and COVID-19 Research
- Photosynthetic Processes and Mechanisms
- Bioactive natural compounds
- Pharmacological Receptor Mechanisms and Effects
- Synthesis of heterocyclic compounds
- Regulation of Appetite and Obesity
- Inorganic and Organometallic Chemistry
- Organic and Inorganic Chemical Reactions
Pfizer (United States)
2015-2025
PRX Research
2024
University of California, Irvine
2017
University of Houston
2015
Duke University
2009-2011
University of New Hampshire
2008
Parsons (United States)
2008
A nickel-catalyzed reductive cross-coupling of alkylpyridinium salts and aryl bromides has been developed using Mn as the reductant. Both primary secondary can be used, high functional group heterocycle tolerance is observed, including for protic groups. Mechanistic studies indicate formation an alkyl radical, controlling its fate was key to success this reaction.
A nickel-catalyzed cross-coupling of benzylic pyridinium salts with arylboronic acids was developed. Coupled chemoselective formation, this method allows benzyl primary amines to be efficiently converted di(hetero)arylmethanes. Excellent heteroaryl and functional group tolerance is observed, a one-pot procedure enables diarylmethanes directly.
It is hypothesized that selective muscarinic M1 subtype activation could be a strategy to provide cognitive benefits schizophrenia and Alzheimer's disease patients while minimizing the cholinergic side effects observed with nonselective orthosteric agonists. Selective of positive allosteric modulator (PAM) has emerged as new approach achieve activation. This manuscript describes development series M1-selective pyridone pyridine amides their key pharmacophores. Compound 38 (PF-06767832) high...
The melanocortin-4 receptor (MC4R) is a centrally expressed, class A GPCR that plays key role in the regulation of appetite and food intake. Deficiencies MC4R signaling result hyperphagia increased body mass humans. Antagonism has potential to mitigate decreased weight loss setting anorexia or cachexia due underlying disease. Herein, we report on identification series orally bioavailable, small-molecule antagonists using focused hit effort optimization these provide clinical candidate 23....
Vaccines and first-generation antiviral therapeutics have provided important protection against COVID-19 caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). However, there remains a need for additional therapeutic options that provide enhanced efficacy potential viral resistance. The SARS-CoV-2 papain-like protease (PL
Recent data demonstrated that activation of the muscarinic M1 receptor by a subtype-selective positive allosteric modulator (PAM) contributes to gastrointestinal (GI) and cardiovascular (CV) cholinergic adverse events (AEs) previously attributed M2 M3 activation. These studies were conducted using PAMs also exhibited agonist activity, leaving open possibility direct agonism, rather than modulation, could be responsible for effects. This article describes design synthesis lactam-derived...
The development of a convergent fragment coupling strategy for the enantioselective total syntheses group rearranged spongian diterpenoids that harbor cis-2,8-dioxabicyclo[3.3.0]octan-3-one unit is described. key bond disconnection relies on late-stage between tertiary carbon radical and an electron-deficient alkene to unite two ring systems form new stereocenters, one which quaternary, in stereoselective efficient manner. This applied toward scalable 14–15 step three diterpenoids,...
A one-pot, four-component Pd-catalyzed coupling has been developed for the synthesis of unsymmetrical 1,2-diketones from aryl halides and alkyl zincs employing tert-butyl isocyanide as a CO source. The intermediate have elaborated to quinoxalines. Mechanistic studies help rationalize high selectivity bis- vs monoinsertion product.
Hydroxysteroid 17-beta-dehydrogenase 13 (HSD17B13) is a hepatic lipid droplet-associated enzyme that upregulated in patients with non-alcoholic fatty liver disease. Recently, there have been several reports predicted loss of function variants HSD17B13 protect against the progression steatosis to steatohepatitis fibrosis and hepatocellular carcinoma. Here we report crystal structures full length complex its NAD+ cofactor, lipid/detergent molecules small molecule inhibitors from two distinct...
A broadly applicable asymmetric synthetic strategy utilizing N-amino cyclic carbamate alkylation that provides access to the various stereochemical permutations of a common structural motif found in many polycyclic polyprenylated acylphloroglucinols is described. The utility this methodology demonstrated through first total synthesis antiviral agent (+)-clusianone.
An asymmetric Mannich reaction of phenylacetate thioesters and sulfonylimines using cinchona alkaloid-based amino (thio)urea catalysts is reported that employs proximity-assisted soft enolization. This approach to enolization based on the cooperative action a carbonyl-activating hydrogen bonding moiety an amine base contained within single catalytic entity facilitate intracomplex deprotonation. Significantly, this allows over range acidity react efficiently, thereby opening door development...
Abstract Vaccines and first-generation antiviral therapeutics have provided important protection against coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome 2 (SARS-CoV-2). However, there remains a need for additional therapeutic options that provide enhanced efficacy potential viral resistance. The SARS-CoV-2 papain-like protease (PL pro ) is one of two essential cysteine proteases involved in replication. While inhibitors the main (M demonstrated clinical...
Several hydroxysteroid dehydrogenase 17-beta 13 variants have previously been identified as protective against metabolic dysfunction-associated steatohepatitis (MASH) fibrosis, ballooning and inflammation, such this target holds significant therapeutic potential. However, over 5 years later, the function of 17B-HSD13 remains unknown. Structure-aided design enables development potent selective sulfonamide-based inhibitors. In order to probe their inhibitory potency in endogenous expression...
The direct addition of enolizable aldehydes and α-halo thioesters to produce β-hydroxy enabled by reductive soft enolization is reported. transformation operationally simple efficient has the unusual feature giving high syn-selectivity, which opposite that produced for (thio)esters under conventional conditions. Moreover, excellent diastereoselectivity results when a chiral nonracemic α-hydroxy aldehyde derivative used.
The Manalpha1,3(Xylbeta1,2)Manalpha structural motif is common to both capsular polysaccharides of Cryptococcus neoformans and cryptococcal glycosphingolipids. Comparative analysis glycosphingolipid profiles in wild-type mutant strains showed that the Xylbeta1,2-transferase (Cxt1p) participates polysaccharide biosynthesis also sole transferase responsible for adding xylose C.
Abstract Experimental and kinetic modelling studies are presented to describe the development of temperature scanning reaction progress protocol for batch reactions. Coupled with graphical manipulations, this approach enables expansion in‐situ from a focus on isothermal concentration profiles include as parameter rapid mechanistic analysis.
Diacylglycerol O-acyltransferase 2 (DGAT2) inhibitors have been shown to lower liver triglyceride content and are being explored clinically as a treatment for non-alcoholic steatohepatitis (NASH). This work details efforts find an extended-half-life DGAT2 inhibitor. A basic moiety was added known inhibitor template, the basicity lipophilicity were fine-tuned by addition of electrophilic fluorines. weakly profile required appropriate balance potency, clearance, permeability. culminated in...
Thioesters undergo soft enolization and direct Mannich addition to sulfonylimines on treatment with magnesium bromide ethyl etherate N,N-diisopropylethylamine. The reactions proceed readily a range of and, in the case 2,4,6-triisopropylphenyl thiopropionate, give moderate good syn diastereoselectivity.
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Abstract The first asymmetric total synthesis of (‐)‐clusianone (I) via Effenberger cyclization is described.
Abstract The direct addition of aldehydes and α‐iodo thioesters provides β‐hydroxy with high syn‐selectivity.