A5065173891- Chemical Synthesis and Analysis
- Sulfur-Based Synthesis Techniques
- X-ray Diffraction in Crystallography
- Crystallization and Solubility Studies
- Peroxisome Proliferator-Activated Receptors
- Catalytic C–H Functionalization Methods
- Synthesis and Reactions of Organic Compounds
- Receptor Mechanisms and Signaling
- Chemical Synthesis and Reactions
- Click Chemistry and Applications
- Synthesis and Biological Evaluation
- Diabetes Treatment and Management
- Synthesis and Catalytic Reactions
- Radical Photochemical Reactions
- Metabolism, Diabetes, and Cancer
- Innovative Microfluidic and Catalytic Techniques Innovation
- Catalytic Alkyne Reactions
- Neuropeptides and Animal Physiology
- Renin-Angiotensin System Studies
- Rings, Modules, and Algebras
- Chemokine receptors and signaling
- Advanced Topics in Algebra
- Melanoma and MAPK Pathways
- Adipose Tissue and Metabolism
- Protein Kinase Regulation and GTPase Signaling
Pfizer (United States)
2014-2025
Foton Motors (China)
2016
Worldwide Clinical Trials (United States)
2015
Spalding University
1997
Merck & Co., Inc., Rahway, NJ, USA (United States)
1996
Texas A&M University
1995
Synaptic Research (United States)
1994
The development of a gold(I)-catalyzed sulfination aryl boronic acids is described. This transformation proceeds through an unprecedented mechanism which exploits the reactivity gold(I)-heteroatom bonds to form sulfinate anions. Further in situ elaboration intermediates leads corresponding sulfones and sulfonamides, two pharmacophores routinely encountered drug discovery.
A mild, efficient synthesis of sulfonyl fluorides from aryl and heteroaryl bromides utilizing palladium catalysis is described.
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...
A series of low-molecular-weight, compact, and multifunctional cyclic alkenylsulfonyl fluorides were efficiently prepared from the corresponding alkenyl triflates. Palladium-catalyzed sulfur dioxide insertion using surrogate reagent DABSO effects sulfinate formation, before trapping with an F electrophile delivers sulfonyl fluorides. broad range functional groups are tolerated, a correspondingly large collection derivatization reactions possible on products, including substitution at sulfur,...
Acetyl-CoA carboxylase (ACC) inhibitors offer significant potential for the treatment of type 2 diabetes mellitus (T2DM), hepatic steatosis, and cancer. However, identification tool compounds suitable to test hypothesis in human trials has been challenging. An advanced series spirocyclic ketone-containing ACC recently reported by Pfizer were metabolized vivo ketone reduction, which complicated pharmacology projections. We disclose that this metabolic reduction can be greatly attenuated...
Abstract The development of a gold(I)‐catalyzed sulfination aryl boronic acids is described. This transformation proceeds through an unprecedented mechanism which exploits the reactivity gold(I)–heteroatom bonds to form sulfinate anions. Further in situ elaboration intermediates leads corresponding sulfones and sulfonamides, two pharmacophores routinely encountered drug discovery.
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,...
Acetyl-CoA carboxylase (ACC) catalyzes the rate-determining step in de novo lipogenesis and plays a crucial role regulation of fatty acid oxidation. Alterations lipid metabolism are believed to contribute insulin resistance; thus inhibition ACC offers promising option for intervention type 2 diabetes mellitus. Herein we disclose series inhibitors based on spirocyclic pyrazololactam core. The lactam has improved chemical metabolic stability relative our previously reported pyrazoloketone...
The editing of organic molecules through single-atom modifications is an enabling capability for medicinal chemistry. While several examples insertions into the carbon–carbon double bonds unsaturated aromatic ring systems have been reported, heteroatom chemically inert single are comparatively rare. We report herein a photochemical strategy formal migration oxygen atoms bonds. This protocol based on ability copper(II) salts to induce homolytic cleavage adjacent alcohols and mediate oxidative...
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...
Abstract A series of low‐molecular‐weight, compact, and multifunctional cyclic alkenylsulfonyl fluorides were efficiently prepared from the corresponding alkenyl triflates. Palladium‐catalyzed sulfur dioxide insertion using surrogate reagent DABSO effects sulfinate formation, before trapping with an F electrophile delivers sulfonyl fluorides. broad range functional groups are tolerated, a correspondingly large collection derivatization reactions possible on products, including substitution...
The first Pd-catalyzed arylation of aza-Achmatowicz rearrangement products with arylboronic acids is achieved, providing versatile 2-aryldihydropyridinones for facile synthesis highly functionalized 2-arylpiperidines. Key to this the use non-phosphine-ligand palladium precatalyst. substrate scope demonstrated >26 examples, and utility illustrated by a small collection 2-arylpiperidines substituents or functional groups at any carbon (C2–C6) as well two NK1 receptor antagonists (+)-CP-999,94...
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,...
We report the successful manufacture of several >50 kg batches a key intermediate via Birch reduction that utilized liquified ammonia as well lithium metal. With an eye toward continued scalability, we explored two alternative procedures to obtain same intermediate: (1) electrochemical performed using continuous flow technology and (2) ketalization approach proceeds with olefin migration give target molecule. Both options were in detail then demonstrated on ≥100 g scale assess overall...
The synthesis of 4',6'-dihydrospiro[piperidine-4,5'-pyrazolo[3,4-c]pyridin]-7'(2'H)-one-based acetyl-CoA carboxylase inhibitors is reported. hitherto unknown N-2 tert-butyl pyrazolospirolactam core was synthesized from ethyl 3-amino-1H-pyrazole-4-carboxylate in a streamlined 10-step requiring only one chromatography procedure. described synthetic strategy provides pyrazolo-fused spirolactams halogenated benzylic arenes and cyclic carboxylates. Key steps include regioselective pyrazole...
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...
The synthesis and structure-activity relationship studies on 5-trifluoromethylpyrido[4,3-d]pyrimidin-4(3H)-ones as antagonists of the human calcium receptor (CaSR) have been recently disclosed [ Didiuk et al. ( 2009 ) Bioorg. Med. Chem. Lett. 19 , 4555 - 4559 ). On basis its pharmacology disposition attributes, (R)-2-(2-hydroxyphenyl)-3-(1-phenylpropan-2-yl)-5-(trifluoromethyl)pyrido[4,3-d]pyrimidin-4(3H)-one (1) was considered for rapid advancement to first-in-human (FIH) trials mitigate...
The synthesis of a series pharmaceutically important N-protected methyl-substituted spirocyclic piperidine-azetidine (2,7-diazaspiro[3.5]nonane) and piperidine-pyrrolidine (2,8-diazaspiro[4.5]decane) ring systems was developed. These motifs contain two differentiated sites (protected secondary amines) to allow for further functionalization via reductive amination, amidation, or other chemistry. spiroazetidine were accessed using nitrile lithiation/alkylation chemistry while the...
The nuclear receptor peroxisome proliferator-activated α (PPARα) is recognized as the primary target of fibrate class hypolipidemic drugs and mediates lipid lowering in part by activating a transcriptional cascade that induces genes involved catabolism lipids. We report here characterization three novel PPARα agonists with therapeutic potential for treating dyslipidemia. These structurally related compounds display potent selective binding to human support robust recruitment coactivator...
Abstract Peptide agonists of the glucagon-like peptide-1 receptor (GLP-1R) have revolutionized diabetes therapy, but their use has been limited by requirement for injection. Here we describe first effective, orally bioavailable small molecule GLP-1R agonists. A sensitized high-throughput screen identified a series that were optimized to promote endogenous signaling with nM potency. These increased insulin levels in primates not rodents, which is explained cryo-EM structure revealed binding...
ADVERTISEMENT RETURN TO ISSUEPREVArticleNEXTNon-peptide angiotensin II receptor antagonists. 1. Design, synthesis, and biological activity of N-substituted indoles dihydroindolesDaljit S. Dhanoa, Scott W. Bagley, Raymond L. Chang, Victor J. Lotti, Tsing Bau Chen, Salah D. Kivlighn, Gloria Zingaro, Peter K. Siegl, Arthur A. Patchett, William GreenleeCite this: Med. Chem. 1993, 36, 26, 4230–4238Publication Date (Print):December 1, 1993Publication History Published online1 May 2002Published...