Deuterium- and tritium-labeled pharmaceutical compounds are pivotal diagnostic tools in drug discovery research, providing vital information about the biological fate of drugs and drug metabolites. ...Herein we demonstrate that a photoredox-mediated hydrogen atom transfer protocol can efficiently and selectively install deuterium (D) and tritium (T) at α-amino sp³ carbon-hydrogen bonds in a single step, using isotopically labeled water (D₂O or T₂O) as the source of hydrogen isotope. In this context, we also report a convenient synthesis of T₂O from T₂, providing access to high-specific-activity T₂O. This protocol has been successfully applied to the high incorporation of deuterium and tritium in 18 drug molecules, which meet the requirements for use in ligand-binding assays and absorption, distribution, metabolism, and excretion studies.
Covering: 1981 to 2019
Natural products continue to play a major role in drug discovery, with half of new chemical entities based structurally on a natural product. Herein, we report a cheminformatic ...analysis of the structural and physicochemical properties of natural product-based drugs in comparison to top-selling brand-name synthetic drugs, and a selection of chemical probes recently discovered from diversity-oriented synthesis libraries. In this analysis, natural product-based drugs covered a broad range of chemical space based on size, polarity, and three-dimensional structure. Natural product-based structures were also more prevalent in top-selling drugs of 2018 compared to 2006. Further, the drugs clustered well according to biosynthetic origins, but less so based on therapeutic classes. Macrocycles occupied distinctive and relatively underpopulated regions of chemical space, while chemical probes largely overlapped with synthetic drugs. This analysis highlights the continued opportunities to leverage natural products and their pharmacophores in modern drug discovery.
Cheminformatic analyses illustrate that drugs from natural product-based and synthetic origins have distinctive structural and physicochemical features. These drugs also cluster by biosynthetic origin and, to some extent, by therapeutic class.
The G-protein-coupled receptors GPR81, GPR109A, and GPR109B share significant sequence homology and form a small group of receptors, each of which is encoded by clustered genes. In recent years, ...endogenous ligands for all three receptors have been described. These endogenous ligands have in common that they are hydroxy-carboxylic acid metabolites, and we therefore have proposed that this receptor family be named hydroxy-carboxylic acid (HCA) receptors. The HCA(1) receptor (GPR81) is activated by 2-hydroxy-propanoic acid (lactate), the HCA(2) receptor (GPR109A) is a receptor for the ketone body 3-hydroxy-butyric acid, and the HCA(3) receptor (GPR109B) is activated by the β-oxidation intermediate 3-hydroxy-octanoic acid. HCA(1) and HCA(2) receptors are found in most mammalian species, whereas the HCA(3) receptor is present only in higher primates. The three receptors have in common that they are expressed in adipocytes and are coupled to G(i)-type G-proteins mediating antilipolytic effects in fat cells. HCA(2) and HCA(3) receptors are also expressed in a variety of immune cells. HCA(2) is a receptor for the antidyslipidemic drug nicotinic acid (niacin) and related compounds, and there is an increasing number of synthetic ligands mainly targeted at HCA(2) and HCA(3) receptors. The aim of this article is to give an overview on the discovery and pharmacological characterization of HCAs, and to introduce an International Union of Basic and Clinical Pharmacology (IUPHAR)-recommended nomenclature. We will also discuss open questions regarding this receptor family as well as their physiological role and therapeutic potential.
Targeting tryptophan is a promising strategy to achieve high levels of selectivity for peptide or protein modification. A chemoselective peptide modification method via photocatalytic tryptophan ...β-position conjugation has been discovered. This transformation has good substrate scope for both peptide and Michael acceptor, and has good chemoselectivity versus other amino acid residues. The endogenous peptides, glucagon and GLP-1 amide, were both successfully conjugated at the tryptophan β-position. Insulin was studied as a nontryptophan control molecule, resulting in exclusive B-chain C-terminal-selective decarboxylative conjugation. This transformation provides a novel approach toward peptide modification to support the discovery of new therapeutic peptides, protein labeling and bioconjugation.
Recent visible-light photoredox catalyzed C(sp3)–C(sp2) cross-coupling provides a novel transformation to potentially enable the synthesis of medicinal chemistry targets. Here, we report a ...profiling study of photocatalytic C(sp3)–C(sp2) cross-coupling, both decarboxylative coupling and cross-electrophile coupling, with 18 pharmaceutically relevant aryl halides by using either Kessil lamp or our newly developed integrated photoreactor. Integrated photoreactor accelerates reaction rate and improves reaction success rate. Cross-electrophile coupling gives higher success rate with broad substrate scope on alkyl halides than that of the decarboxylative coupling. In addition, a successful application example on a discovery program demonstrates the efficient synthesis of medicinal chemistry targets via photocatalytic C(sp3)–C(sp2) cross-coupling by using our integrated photoreactor.
Emergence of bacterial resistance is a major issue for all classes of antibiotics; therefore, the identification of new classes is critically needed. Recently we reported the discovery of ...platensimycin by screening natural product extracts using a target-based whole-cell strategy with antisense silencing technology in concert with cell free biochemical validations. Continued screening efforts led to the discovery of platencin, a novel natural product that is chemically and biologically related but different from platensimycin. Platencin exhibits a broad-spectrum Gram-positive antibacterial activity through inhibition of fatty acid biosynthesis. It does not exhibit cross-resistance to key antibiotic resistant strains tested, including methicillin-resistant Staphylococcus aureus, vancomycin-intermediate S. aureus, and vancomycin-resistant ENTEROCOCCI: Platencin shows potent in vivo efficacy without any observed toxicity. It targets two essential proteins, β-ketoacyl-acyl carrier protein (ACP) synthase II (FabF) and III (FabH) with IC₅₀ values of 1.95 and 3.91 μg/ml, respectively, whereas platensimycin targets only FabF (IC₅₀ = 0.13 μg/ml) in S. aureus, emphasizing the fact that more antibiotics with novel structures and new modes of action can be discovered by using this antisense differential sensitivity whole-cell screening paradigm.
Clinical studies indicate that partial agonists of the G-protein-coupled, free fatty acid receptor 1 GPR40 enhance glucose-dependent insulin secretion and represent a potential mechanism for the ...treatment of type 2 diabetes mellitus. Full allosteric agonists (AgoPAMs) of GPR40 bind to a site distinct from partial agonists and can provide additional efficacy. We report the 3.2-Å crystal structure of human GPR40 (hGPR40) in complex with both the partial agonist MK-8666 and an AgoPAM, which exposes a novel lipid-facing AgoPAM-binding pocket outside the transmembrane helical bundle. Comparison with an additional 2.2-Å structure of the hGPR40-MK-8666 binary complex reveals an induced-fit conformational coupling between the partial agonist and AgoPAM binding sites, involving rearrangements of the transmembrane helices 4 and 5 (TM4 and TM5) and transition of the intracellular loop 2 (ICL2) into a short helix. These conformational changes likely prime GPR40 to a more active-like state and explain the binding cooperativity between these ligands.
GPR40 agonists are effective antidiabetic agents believed to lower glucose through direct effects on the beta cell to increase glucose stimulated insulin secretion. However, not all GPR40 agonists ...are the same. Partial agonists lower glucose through direct effects on the pancreas, whereas GPR40 AgoPAMs may incorporate additional therapeutic effects through increases in insulinotrophic incretins secreted by the gut. Here we describe how GPR40 AgoPAMs stimulate both insulin and incretin secretion in vivo over time in diabetic GK rats. We also describe effects of AgoPAMs in vivo to lower glucose and body weight beyond what is seen with partial GPR40 agonists in both the acute and chronic setting. Further comparisons of the glucose lowering profile of AgoPAMs suggest these compounds may possess greater glucose control even in the presence of elevated glucagon secretion, an unexpected feature observed with both acute and chronic treatment with AgoPAMs. Together these studies highlight the complexity of GPR40 pharmacology and the potential additional benefits AgoPAMs may possess above partial agonists for the diabetic patient.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Nicotinic acid (niacin) induces beneficial changes in serum lipoproteins and has been associated with beneficial cardiovascular effects. Niacin reduces low-density lipoprotein, increases high-density ...lipoprotein, and decreases triglycerides. It is well established that activation of the seven-transmembrane G(i)-coupled receptor GPR109A on Langerhans cells results in release of prostaglandin D₂, which mediates the well-known flushing side effect of niacin. Niacin activation of GPR109A on adipocytes also mediates the transient reduction of plasma free fatty acid (FFA) levels characteristic of niacin, which has been long hypothesized to be the mechanism underlying the changes in the serum lipid profile. We tested this "FFA hypothesis" and the hypothesis that niacin lipid efficacy is mediated via GPR109A by dosing mice lacking GPR109A with niacin and testing two novel, full GPR109A agonists, MK-1903 and SCH900271, in three human clinical trials. In mice, the absence of GPR109A had no effect on niacin's lipid efficacy despite complete abrogation of the anti-lipolytic effect. Both MK-1903 and SCH900271 lowered FFAs acutely in humans; however, neither had the expected effects on serum lipids. Chronic FFA suppression was not sustainable via GPR109A agonism with niacin, MK-1903, or SCH900271. We conclude that the GPR109A receptor does not mediate niacin's lipid efficacy, challenging the long-standing FFA hypothesis.
The palladium-catalyzed Suzuki−Miyaura coupling of pyridyl-2-boronic esters provided an efficient approach to useful biaryl building blocks containing a 2-pyridyl moiety. The convenient reaction ...protocol demonstrates its potentially wide applications in medicinal chemistry.
PDF
