A5023487227- Chemical Synthesis and Analysis
- Receptor Mechanisms and Signaling
- X-ray Diffraction in Crystallography
- Crystallization and Solubility Studies
- Asymmetric Synthesis and Catalysis
- Chemical Synthesis and Reactions
- Diabetes Treatment and Management
- Computational Drug Discovery Methods
- Synthetic Organic Chemistry Methods
- Carbohydrate Chemistry and Synthesis
- Pancreatic function and diabetes
- Microbial Natural Products and Biosynthesis
- Neuropeptides and Animal Physiology
- Lipoproteins and Cardiovascular Health
- Click Chemistry and Applications
- RNA and protein synthesis mechanisms
- RNA Research and Splicing
- Molecular spectroscopy and chirality
- Catalytic C–H Functionalization Methods
- Protein Structure and Dynamics
- Chemokine receptors and signaling
- Catalytic Cross-Coupling Reactions
- Analytical Chemistry and Chromatography
- Chemical synthesis and alkaloids
- Various Chemistry Research Topics
Pfizer (United States)
2014-2023
Foton Motors (China)
2012-2017
Scripps Research Institute
2013
University of Michigan
2002
The University of Texas at Austin
1996-1999
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...
As the need for novel antibiotic classes to combat bacterial drug resistance increases, paucity of leads resulting from target-based antibacterial screening pharmaceutical compound libraries is major concern. One explanation this lack success that efforts have not leveraged eukaryotic bias more extensive chemistry targeting gene families such as G protein-coupled receptors and protein kinases. Consistent with a focus on target space resembling these targets, we used whole-cell identify...
Macrocyclic peptides are considered large enough to inhibit "undruggable" targets, but the design of passively cell-permeable molecules in this space remains a challenge due poorly understood role molecular size on passive membrane permeability. Using split-pool combinatorial synthesis, we constructed library cyclic, per-N-methlyated spanning wide range calculated lipohilicities (0 < AlogP 8) and weights (∼800 Da MW ∼1200 Da). Analysis by parallel artificial permeability assay revealed steep...
The impact of side chain functionality on the pharmacokinetics an orally bioavailable cyclic peptide scaffold is investigated.
A highly efficient macrocyclization reaction has been developed via the palladium-catalyzed C-H arylation of side-chains tryptophan with halophenyl-containing amino acids. This method allows for direct access to 15- 25-membered biaryl macrocycles in 40-75% yield, at moderate concentration, proceeding exclusively C-2 position indole.
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...
The effect of peptide-to-peptoid substitutions on the passive membrane permeability an N-methylated cyclic hexapeptide is examined. In general, maintained but increased conformational heterogeneity. Diversification with nonproteinogenic side chains up to 3-fold. Additionally, impact peptoid within a β-turn are explored. Based these results, strategic incorporation residues into peptides can maintain or improve cell permeability, while increasing access diverse side-chain functionality.
The chemokine receptor CXCR7 is an attractive target for a variety of diseases. While several small-molecule modulators have been reported, peptidic macrocycles may provide advantages in terms potency, selectivity, and reduced off-target activity. We produced series that incorporate N-linked peptoid functionality where the group enabled us to explore side-chain diversity well beyond natural amino acids. At same time, theoretical calculations experimental assays were used track reduce...
A general method for constraining peptide conformations via linkage of aromatic sidechains has been developed. Macrocyclization suitably functionalized tri-, tetra- and pentapeptides Suzuki-Miyaura cross-coupling used to generate side chain chain, biaryl-bridged 14- 21-membered macrocyclic peptides. Biaryl bridges possessing three different configurations, meta-meta, meta-ortho, ortho-meta, were systematically explored through regiochemical variation the aryl halide boronate coupling...
This paper describes the design and synthesis of a novel series dual inhibitors acetyl-CoA carboxylase 1 2 (ACC1 ACC2). Key findings include discovery an initial lead that was modestly potent subsequent medicinal chemistry optimization with focus on lipophilic efficiency (LipE) to balance overall druglike properties. Free-Wilson methodology provided clear breakdown contributions specific structural elements LipE, rationale for prioritization virtual compounds synthesis, highly successful...
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...
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 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,...
Sickle cell disease (SCD) is a genetic disorder caused by single point mutation (β6 Glu → Val) on the β-chain of adult hemoglobin (HbA) that results in sickled (HbS). In deoxygenated state, polymerization HbS leads to sickling red blood cells (RBC). Several downstream consequences and RBC include vaso-occlusion, hemolytic anemia, stroke. We report design noncovalent modulator HbS, clinical candidate PF-07059013 (23). The seminal hit molecule was discovered virtual screening confirmed through...
Cyclic peptides have long tantalized drug designers with their potential ability to combine the best attributes of antibodies and small molecules. An ideal cyclic peptide candidate would be able recognize a protein surface like an antibody while achieving oral bioavailability molecule. It has been hypothesized that such balance permeability solubility using solvent-dependent conformational flexibility. Herein we report deconvolution NMR methodology combines residual dipolar couplings,...
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...
Previous studies have revealed that the glucoincretin hormone glucagon-like peptide-1 (GLP-1)(7-36)amide is metabolized by dipeptidyl peptidase-IV (DPP-IV) and neutral endopeptidase 24.11 (NEP) to yield GLP-1(9-36)amide GLP-1(28-36)amide, respectively, as principal metabolites. Contrary previous notion GLP-1(7-36)amide metabolites are pharmacologically inactive, recent demonstrated cardioprotective insulinomimetic effects with both GLP-1(28-36)amide in animals humans. In present work, we...
The synthesis and <italic>in vivo</italic> pharmacokinetic profile of an analogue cyclosporine is disclosed.
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...
Conditions have been identified for the efficient Ullmann macrocyclization of phenol and imidazole nucleophiles with aryl iodides at high reaction concentrations up to 100 mM using 5-10 mol % loading an inexpensive copper catalyst. A range substitution patterns ring sizes are tolerated, method has exemplified by synthesis a set druglike macrocycles.