A5011949689- Receptor Mechanisms and Signaling
- RNA Research and Splicing
- Estrogen and related hormone effects
- RNA and protein synthesis mechanisms
- Liver Disease Diagnosis and Treatment
- Hormonal Regulation and Hypertension
- Muscle Physiology and Disorders
- Drug Transport and Resistance Mechanisms
- Genetics, Aging, and Longevity in Model Organisms
- Computational Drug Discovery Methods
- Neuropeptides and Animal Physiology
- Diabetes Treatment and Management
- RNA modifications and cancer
- Pancreatic function and diabetes
- Lipoproteins and Cardiovascular Health
- interferon and immune responses
- Hepatitis C virus research
- Ubiquitin and proteasome pathways
- Biochemical Analysis and Sensing Techniques
- Regulation of Appetite and Obesity
- Muscle metabolism and nutrition
- Signaling Pathways in Disease
- X-ray Diffraction in Crystallography
- Inflammatory mediators and NSAID effects
- Melanoma and MAPK Pathways
Pfizer (United States)
2014-2024
University of Modena and Reggio Emilia
2005-2010
Azienda Unita' Sanitaria Locale Di Modena
2010
Stichting HIV Monitoring
2009
Columbia University
2003-2005
University of Chicago
1998
May Institute
1998
Peptide agonists of the glucagon-like peptide-1 receptor (GLP-1R) have revolutionized diabetes therapy, but their use has been limited because they require injection. Herein, we describe discovery orally bioavailable, small-molecule, GLP-1R agonist PF-06882961 (danuglipron). A sensitized high-throughput screen was used to identify 5-fluoropyrimidine-based that were optimized promote endogenous signaling with nanomolar potency. Incorporation a carboxylic acid moiety provided considerable...
The objective of this study was to examine the effects short-term exercise training, myostatin inhibition (PF-354), and + PF-354, all relative a vehicle control, on performance metabolic measures in 24-month-old mice. At termination, PF-354–treated mice exhibited significantly greater muscle weights. Performance revealed that PF-354 increased treadmill running time distance exhaustion (more than twofold) habitual activity. Measures strength were not different; however, treatment groups...
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...
For a motor unit to function, neurons and muscle cells need adopt their correct cell fate, form appropriate cellular contacts, assemble specific repertoire of signaling proteins into presynaptic postsynaptic structures. In the nematode Caenorhabditis elegans , disruption any these steps causes uncoordinated locomotory behavior ( unc phenotype). We report here positional cloning new gene, unc-122 which we show by mosaic analysis tissue-specific rescue experiments act in affect behavior. codes...
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...
Citrate is a key regulatory metabolic intermediate as it facilitates the integration of glycolysis and lipid synthesis pathways. Inhibition hepatic extracellular citrate uptake, by blocking sodium-coupled transporter (NaCT or SLC13A5), has been suggested potential therapeutic approach to treat disorders. NaCT transports from blood into cell coupled transport sodium ions. The studies herein report identification characterization novel small dicarboxylate molecule (compound 2) capable...
The mineralocorticoid receptor (MR) antagonists PF 03882845 and eplerenone were evaluated for renal protection against aldosterone mediated disease in uninephrectomized Sprague Dawley (SD) rats maintained on a high salt diet receiving by osmotic mini pump 27 days. Serum K+ the urinary albumin to creatinine ratio (UACR) assessed following 14 days of treatment. Aldosterone induced fibrosis as evidenced increases UACR, collagen IV staining kidney cortex, expression pro fibrotic genes relative...
Abstract Background Accumulating evidence supports the role of mineralocorticoid receptor (MR) in pathogenesis diabetic nephropathy. These findings have generated renewed interest novel MR antagonists with improved selectivity against other nuclear hormone receptors and a potentially reduced risk hyperkalemia. Characterization warrants establishing translatable biomarkers activity at receptor. We assessed translatability urinary sodium to potassium ratio (Na + /K ) plasma aldosterone as...
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....
Cyclic constraints are incorporated into an 11-residue analogue of the N-terminus glucagon-like peptide-1 (GLP-1) to investigate effects structure on agonist activity. Cyclization through linking side chains residues 2 and 5 or 9 produced agonists at nM concentrations in a cAMP assay. 2D NMR CD spectra revealed N-terminal β-turn C-terminal helix that differentially influenced affinity potency. These structures can inform development small molecule GLP-1 receptor treat type diabetes.
Abstract Glycogen synthase (GYS1) is the central enzyme in muscle glycogen biosynthesis. GYS1 activity inhibited by phosphorylation of its amino (N) and carboxyl (C) termini, which relieved allosteric activation glucose-6-phosphate (Glc6P). We present cryo-EM structures at 3.0–4.0 Å resolution phosphorylated human GYS1, complex with a minimal interacting region glycogenin, inhibited, activated catalytically competent states. Phosphorylations specific terminal residues are sensed different...
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...
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...
Precise regulation of Type I interferon signaling is crucial for combating infection and cancer while avoiding autoimmunity. negatively regulated by USP18. USP18 cleaves ISG15, an interferon-induced ubiquitin-like modification, via its canonical catalytic function, inhibits receptor activity through scaffold role.
Sodium-phosphate cotransporter 2a, or NaPi2a (SLC34A1), is a solute-carrier (SLC) transporter located in the kidney proximal tubule that reabsorbs glomerular-filtered phosphate. Inhibition of may enhance urinary phosphate excretion and correct maladaptive mineral hormonal derangements associated with increased cardiovascular risk chronic disease–mineral bone disorder (CKD-MBD). To date, only nonselective NaPi inhibitors have been described. Herein, we detail discovery first series selective...
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...