A5035499749- Catalytic C–H Functionalization Methods
- Synthesis and Catalytic Reactions
- Asymmetric Hydrogenation and Catalysis
- Synthetic Organic Chemistry Methods
- Pancreatic function and diabetes
- Catalytic Alkyne Reactions
- Synthesis and Biological Evaluation
- Cyclopropane Reaction Mechanisms
- Fluorine in Organic Chemistry
- Chemical Synthesis and Analysis
- Protein Degradation and Inhibitors
- Lipid metabolism and biosynthesis
- X-ray Diffraction in Crystallography
- Ubiquitin and proteasome pathways
- Crystallization and Solubility Studies
- Metabolism, Diabetes, and Cancer
- Gaussian Processes and Bayesian Inference
- Receptor Mechanisms and Signaling
- Advanced Synthetic Organic Chemistry
- Synthesis of β-Lactam Compounds
- Liver Disease Diagnosis and Treatment
- Synthesis and Reactions of Organic Compounds
- Neural dynamics and brain function
- Neural Networks and Applications
- Synthesis and Reactivity of Heterocycles
Pfizer (United States)
2015-2024
Stony Brook University
2023
Foton Motors (China)
2016
University of California, Irvine
2009-2012
Novartis (United Kingdom)
2012
Irvine University
2011
Adenosine monophosphate-activated protein kinase (AMPK) is a involved in maintaining energy homeostasis within cells. On the basis of human genetic association data, AMPK activators were pursued for treatment diabetic nephropathy. Identification an indazole amide high throughput screening (HTS) hit followed by truncation to its minimal pharmacophore provided acid lead compound. Optimization core and aryl appendage improved oral absorption culminated identification indole acid, PF-06409577...
The medicinal chemistry and preclinical biology of imidazopyridine-based inhibitors diacylglycerol acyltransferase 2 (DGAT2) is described. A screening hit 1 with low lipophilic efficiency (LipE) was optimized through two key structural modifications: (1) identification the pyrrolidine amide group for a significant LipE improvement, (2) insertion sp(3)-hybridized carbon center in core molecule simultaneous improvement N-glucuronidation metabolic liability off-target pharmacology. candidate 9...
Increased fructose consumption and its subsequent metabolism have been implicated in metabolic disorders such as nonalcoholic fatty liver disease steatohepatitis (NAFLD/NASH) insulin resistance. Ketohexokinase (KHK) converts to fructose-1-phosphate (F1P) the first step of cascade. Herein we report discovery a first-in-class KHK inhibitor, PF-06835919 (8), currently phase 2 clinical trials. The 8 was built upon our originally reported, fragment-derived lead 1 recognition an alternative,...
Myeloperoxidase (MPO) is a heme peroxidase that catalyzes the production of hypochlorous acid. Clinical evidence suggests causal role for MPO in various autoimmune and inflammatory disorders including vasculitis cardiovascular Parkinson's diseases, implying inhibitors may represent therapeutic treatment option. Herein, we present design, synthesis, preclinical evaluation N1-substituted-6-arylthiouracils as potent selective MPO. Inhibition proceeded time-dependent manner by covalent,...
A chemical probe (PFI-7) for the Gid4 subunit of human E3 ligase CTLH degradation complex.
Increased fructose consumption and its subsequent metabolism have been implicated in hepatic steatosis, dyslipidemia, obesity, insulin resistance humans. Since ketohexokinase (KHK) is the principal enzyme responsible for metabolism, identification of a selective KHK inhibitor may help to further elucidate effect inhibition on these metabolic disorders. Until now, studies with small molecules limited due lack viable vivo pharmacological tools. Herein we report discovery 12, potency properties...
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...
Aryl bromides are known to be challenging substrates in the decarboxylative cross-electrophile coupling with redox-active NHP esters-the majority of such processes utilize aryl iodides. Herein, we describe development conditions that suitable for esters and a wide range (hetero)aryl bromides. The key advances allowed use this reaction (1) identification ligand L3 as an optimal electron-neutral deficient (2) significant improvement yield iodide salts excess heterogenous zinc impart reaction....
The development of a strategy consisting allylsilane ring-closing metathesis and subsequent SE′ electrophilic desilylation (allylsilane RCM/SE′) to construct exo-methylidenecycloalkanes is described. Its utility documented in short syntheses teucladiol poitediol. A key transformation the synthesis an aldol addition that establishes three stereochemical relationships one step with ≥10:1 diastereoselectivity provides fascinating example double stereodifferentiation/kinetic resolution racemic...
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...
G protein-coupled receptors (GPCRs) modulate diverse cellular signaling pathways and are important drug targets. Despite the availability of high-resolution structures, discovery allosteric modulators remains challenging due to dynamic nature GPCRs in native membranes. We developed a strategy covalently tether fragments adjacent sites enhance their potency enable fragment-based screening cell-based systems. employed genetic code expansion site-specifically introduce noncanonical amino acids...
Abstract The CTLH complex is a multi-subunit ubiquitin ligase that recognizes substrates with Pro/N-degrons via the substrate receptor GID4. Recently, focus has turned to this as potential mediator of targeted protein degradation, but role GID4-mediated ubiquitylation and proteasomal degradation plays in humans thus far remained unclear. Here, we report PFI-7, potent, selective, cell-active chemical probe antagonizes Pro/N-degron binding human Use PFI-7 proximity-dependent biotinylation...
In a short synthesis of echinopine B, guaiane-like intermediate was generated through methylenecyclopentane annulation onto substituted cycloheptenone. The resulting bicyclic compound converted into the natural product by PtCl2-catalyzed enyne cycloisomerization (see scheme). Several late-stage polycyclic rearrangement products were isolated and characterized. Detailed facts importance to specialist readers are published as ”Supporting Information”. Such documents peer-reviewed, but not...
Preclinical and clinical data suggest that acetyl-CoA carboxylase (ACC) inhibitors have the potential to rebalance disordered lipid metabolism, leading improvements in nonalcoholic steatohepatitis (NASH). Consistent with these observations, first-in-human trials our ACC inhibitor PF-05175157 led robust reduction of de novo lipogenesis (DNL), albeit concomitant reductions platelet count, which were attributed inhibition fatty acid synthesis within bone marrow. Herein, we describe design,...
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...
A general strategy for the synthesis of exo-methylidenecycloalkanes, which are salient features many terpenoid natural products, is presented. Ring-closing alkene metathesis allylsilanes provides intermediates that can be protodesilylated with transposition to afford exocyclic alkene; alternatively, reactivity cyclic allylsilane intermediate harnessed introduce allylic functionality. These two modes showcased in short syntheses sesquiterpene products teucladiol and poitediol, respectively.
Two orthogonal routes for preparing (S)-2-methylazetidine as a bench stable, crystalline (R)-(-)-CSA salt are presented. One route features the in situ generation and cyclization of 1,3-bis-triflate to form azetidine ring, while second involves chemoselective reduction N-Boc azetidine-2-carboxylic acid. Both sequences afford desired product good overall yields (61% 49%) high enantiomeric excess (>99% ee), avoid column chromatography, suitable large-scale production this material.
A straightforward method for preparing 3,6-disubstituted-1,2,4-triazines through a redox-efficient cyclodehydration of β-keto- N-acylsulfonamides with hydrazine salts is described. Two approaches synthesizing the requisite are presented, which allow late stage incorporation either C3 or C6 substituent in flexible manner from acid chlorides α-bromoketones, respectively. The scope this methodology includes primary and secondary sp3-linked substituents at both positions, mild reaction...
Optimization of the pharmacokinetic (PK) properties a series activators adenosine monophosphate-activated protein kinase (AMPK) is described. Derivatives previously described 5-aryl-indole-3-carboxylic acid clinical candidate (1) were examined with goal reducing glucuronidation rate and minimizing renal excretion. Compounds 10 (PF-06679142) 14 (PF-06685249) exhibited robust activation AMPK in rat kidneys as well desirable oral absorption, low plasma clearance, negligible clearance...
Indole acids 1, 2, and 3 are potent 5′-adenosine monophosphate-activated protein kinase (AMPK) activators for the potential treatment of diabetic nephropathy. Compounds 1–3 were scaled to supply material preclinical studies, indole was selected advancement first-in-human clinical trials kilogram quantities. The progression synthesis strategy these AMPK is described, as routes efficient structure–activity relationship generation then improved larger scales. developed sequences employed...
Abstract We have developed a novel chemical handle (PFI-E3H1) and probe (PFI-7) as ligands for the Gid4 subunit of human E3 ligase CTLH degradation complex. Through an efficient initial hit-ID campaign, structure-based drug design (SBDD) leveraging sizeable Pfizer compound library, we identified 500 nM ligand this through file screening alone. Further exploration vector that is tolerant to addition linker future chimeric molecule design. The chemotype was subsequently optimized sub-100...
DiscoverRx's PathHunter™ assay measures GPCR agonist potency, via the recruitment of β-arrestin, independent subtype G(α) protein activated. This is frequently used in drug discovery although little known about pharmacology generated. Here we have compared efficacy and affinity values obtained assays with those from more established radioligand binding functional techniques.Using cells expressing human sphingosine-1-phosphate S1P(3) receptor at four different densities, pharmacological...
Preclinical pharmacokinetic, efficacy, and toxicology results are reported for a series of DGAT2 inhibitors the potential treatment hypertriglyceridemia.