A5084732640- Chemical Synthesis and Analysis
- Catalytic C–H Functionalization Methods
- Crystallization and Solubility Studies
- RNA Research and Splicing
- X-ray Diffraction in Crystallography
- RNA and protein synthesis mechanisms
- Receptor Mechanisms and Signaling
- Catalytic Cross-Coupling Reactions
- Synthesis of heterocyclic compounds
- Asymmetric Hydrogenation and Catalysis
- Lipoproteins and Cardiovascular Health
- Synthesis and Biological Evaluation
- Chemical synthesis and alkaloids
- Click Chemistry and Applications
- Protein Degradation and Inhibitors
- Synthesis and Characterization of Heterocyclic Compounds
- RNA modifications and cancer
- Synthesis and Catalytic Reactions
- Advanced Synthetic Organic Chemistry
- Marine Sponges and Natural Products
- Neuropeptides and Animal Physiology
- Chemokine receptors and signaling
- Biochemical and Structural Characterization
- Synthesis and Reactivity of Sulfur-Containing Compounds
- Synthesis and biological activity
Pfizer (United States)
2013-2023
GlaxoSmithKline (United Kingdom)
2008
University of Mississippi
2006-2007
University of Pennsylvania
2006-2007
A general and facile one-pot amination procedure for the synthesis of 2-aminopyridines from corresponding pyridine-N-oxides is presented as a mild alternative to S(N)Ar chemistry. variety amines heterocyclic-N-oxides participate effectively in this transformation which uses phosphonium salt, PyBroP, means substrate activation.
A general and facile one-pot procedure for the synthesis of 2-substituted pyridines from corresponding pyridine-N-oxides nucleophiles is presented as a mild alternative to SNAr chemistry. variety heterocyclic-N-oxides participate effectively in this transformation, which uses phosphonium salt, PyBroP, means substrate activation.
Proprotein convertase subtilisin/kexin type 9 (PCSK9) plays a key role in regulating the levels of plasma low-density lipoprotein cholesterol (LDL-C). Here, we demonstrate that compound PF-06446846 inhibits translation PCSK9 by inducing ribosome to stall around codon 34, mediated sequence nascent chain within exit tunnel. We further show reduces and total rats following oral dosing. Using profiling, is highly selective for inhibition translation. The mechanism action employed reveals...
The identification of potent, highly selective orally bioavailable ghrelin receptor inverse agonists from a spiro-azetidino-piperidine series is described. Examples this have promising in vivo pharmacokinetics and increase glucose-stimulated insulin secretion human whole dispersed islets. A physicochemistry-based strategy to lipophilic efficiency for potency retain low clearance satisfactory permeability while reducing off-target pharmacology led the discovery 16h. Compound 16h has superior...
Compounds that contain the 1-heteroaryl-3-azabicyclo[3.1.0]hexane architecture are of particular interest to pharmaceutical industry yet remain a challenge synthesize. We report herein an expedient and modular approach synthesis 1-heteroaryl-3-azabicyclo[3.1.0]hexanes by Suzuki–Miyaura Chan–Evans–Lam coupling reactions tertiary trifluoroborate salts. Our cross-coupling protocol is compatible with broad range aryl heteroaryl bromides chlorides. The unprecedented trifluoroborates allows facile...
The heteroaryl ether is an important structural feature in molecules of biological interest, yet it remains a challenge to synthesize. A new and practical method for the synthesis ethers reported. In presence PyBroP, variety nonaromatic alcohols readily add azine N-oxides afford corresponding ethers. reaction conditions are mild, economical, chemoselective, compatible with broad range substrates. Thirty-eight examples provided, as discussion optimization mechanism.
A new and useful procedure for the macrocyclization of linear peptides is described. The natural amino acid side chains tyrosine (phenol), lysine (alkylamine), histidine (imidazole) react in an intramolecular fashion with a pendent pyridine-N-oxide-carboxamide, which selectively activated by phosphonium salt, PyBroP. reaction mild, rapid, efficient potentially large substrate scope. Multiple examples are provided full characterization analyses, including novel aza-variant C-O-D ring system...
Takeda G-protein-coupled receptor 5 (TGR5) represents an exciting biological target for the potential treatment of diabetes and metabolic syndrome. A new class high-throughput screening (HTS)-derived tetrahydropyrido[4,3-d]pyrimidine amide TGR5 agonists is disclosed. We describe our effort to identify orally available agonist suitable assessment systemic agonism. This resulted in identification 16, which had acceptable potency pharmacokinetic properties allow vivo dog. key aspect this work...
A new and expedient synthesis of α-(2-azaheteroaryl) acetates is presented. The reaction proceeds rapidly under mild conditions via the addition silyl ketene acetals to azine-N-oxides in presence phosphonium salt PyBroP. This procedure affords diverse which are highly desirable components/building blocks molecules pharmaceutical interest but traditionally challenging synthesize contemporary methods. optimization mechanism as well a novel electronically enhanced PyBroP derivative described.
Abstract Targeting of the human ribosome is an unprecedented therapeutic modality with a genome‐wide selectivity challenge. A liver‐targeted drug candidate described that inhibits ribosomal synthesis PCSK9, lipid regulator considered undruggable by small molecules. Key to concept was identification pharmacologically active zwitterions designed be retained in liver. Oral delivery poorly permeable achieved prodrugs susceptible cleavage carboxylesterase 1. The select tetrazole crucial....
The optimization of a new class small molecule PCSK9 mRNA translation inhibitors is described. potency, physicochemical properties, and off-target pharmacology associated with the hit compound (1) were improved by changes to two regions molecule. last step in synthesis congested amide center was enabled three different routes. Subtle structural yielded significant margins. These efforts led identification 7l 7n overall profiles suitable for vivo evaluation. In 14-day toxicology study,...
Discovery efforts leading to the identification of ervogastat (PF-06865571), a systemically acting diacylglycerol acyltransferase (DGAT2) inhibitor that has advanced into clinical trials for treatment non-alcoholic steatohepatitis (NASH) with liver fibrosis, are described herein. Ervogastat is first-in-class DGAT2 addressed potential development risks prototype liver-targeted PF-06427878. Key design elements culminated in discovery (1) replacement metabolically labile motif 3,5-disubstituted...
Manzamine A represents an important lead structure for the development of novel antimalarial chemotherapies. The synthesis and biological evaluation a group simplified analogues manzamine A, which were designed to examine roles D rings both relative stereochemistry orientation β-carboline heterocycle on activity are described.
Recent studies in adipose tissue, pancreas, muscle, and macrophages suggest that MAP4K4, a serine/threonine protein kinase may be viable target for antidiabetic drugs. As part of the evaluation MAP4K4 as novel target, tool compound, 16 (PF-6260933) lead 17 possessing excellent kinome selectivity suitable properties were delivered to establish proof concept vivo. The medicinal chemistry effort led discovery these compounds is described herein together with vivo pharmacokinetic activity model...
Pyridine-<i>N</i>-oxides are often used as reactive precursors in the syntheses of substituted pyridines. Isolation and subsequent reduction associated pyridine-<i>N</i>-oxide intermediates can be challenging. We have discovered that tetrahydroxydiboron functions a mild, versatile, remarkably selective reducing agent for pyridine-<i>N</i>-oxides may an situ fashion, thus obviating isolation <i>N</i>-oxide-containing
A series of small-molecule YEATS4 binders have been discovered as part an ongoing research effort to generate high-quality probe molecules for emerging and/or challenging epigenetic targets. Analogues such 4d and 4e demonstrate excellent potency selectivity binding versus YEATS1,2,3 exhibit good physical properties in vitro safety profiles. new X-ray crystal structure confirms direct this chemical at the lysine acetylation recognition site YEATS domain. Multiple analogues engage with...
The synthesis and biological evaluation of a series analogues manzamine A, representing partial structures the pentacyclic ABCDE diamine core, is described. All new compounds were screened against Plasmodium falciparum demonstrated attenuated antimalarial activity relative to that A.
C-X-C chemokine receptor type 7 (CXCR7) is involved in cardiac and immune pathophysiology. We report the discovery of a novel 1,4-diazepine CXCR7 modulator, demonstrating for first time role pharmacological intervention repair. Structure-activity-relationship (SAR) studies demonstrated that net reduction lipophilicity (log D) an incorporation saturated ring systems yielded compounds with good potencies improvements oxidative metabolic stability human-liver microsomes (HLM). Tethering...
A method for the modular synthesis of α-heteroaryl piperidines is reported. The two-step procedure consists an initial Pd-catalyzed Suzuki cross-coupling heteroaryl bromide with a boronate ester derived from N-Boc piperidone, followed by subsequent tetrahydropyridine reduction. Using this method, piperidine products featuring broad range pharmaceutically relevant azine and diazine substitutions have been prepared.
A strategy for the structural modification of biologically important alkene-containing natural products via ring-opening olefin metathesis is described. Exposure manzamine 1 to second-generation Grubbs catalyst in presence ethylene leads formation 2 and 4. The antibacterial activity novel analogue (IC50 = 0.10 nM) against Mycobacterium intracellulare ca. 2-fold more potent than that ciprofloxacin 0.18 nM), a drug frequently used antibiotic-resistant infections.
Inhibition of triacylglycerol (TAG) biosynthetic enzymes has been suggested as a promising strategy to treat insulin resistance, diabetes, dyslipidemia, and hepatic steatosis. Monoacylglycerol acyltransferase 3 (MGAT3) is an integral membrane enzyme that catalyzes the acylation both monoacylglycerol (MAG) diacylglycerol (DAG) generate DAG TAG, respectively. Herein, we report discovery characterization first selective small molecule inhibitors MGAT3. Isoindoline-5-sulfonamide (6f,...
Molecules containing trifluoromethoxyaryl groups are of interest in pharmaceutical, agrochemical, and materials science research, due to their unique physical electronic properties. Many the known methods synthesize aryl trifluoromethyl ethers require harsh reagents highly controlled reaction conditions rarely occur when heteroaromatic units present. The two-step O-trifluoromethylation phenols via xanthates is one such method that suffers from these drawbacks. Herein, we report a for...