Superoxide produced by mitochondrial site I inactivates cardiac succinate dehydrogenase and induces hepatic steatosis in Sod2 knockout mice.

Superoxide produced by mitochondria has been implicated in numerous physiologies and pathologies. Eleven different mitochondrial sites that can produce superoxide and/or hydrogen peroxide (O/HO) have been identified in vitro, but little is known about their contributions in vivo. We introduce novel variants of S1QELs and S3QELs (small molecules that suppress O/HO production specifically from mitochondrial sites I and III, respectively, without compromising bioenergetics), that are suitable for use in vivo.

Optimization of Preclinical Metabolism for Somatostatin Receptor Subtype 5-Selective Antagonists.

A series of structurally diverse azaspirodecanone and spirooxazolidinone analogues were designed and synthesized as potent and selective somatostatin receptor subtype 5 (SSTR5) antagonists. Four optimized compounds each representing a subseries showed improvement in their metabolic stability and pharmacokinetic profiles compared to those of the original lead compound while maintaining pharmacodynamic efficacy. The optimized cyclopropyl analogue demonstrated efficacy in a mouse oral glucose tolerance test and an improved metabolic profile and pharmacokinetic properties in rhesus monkey studies.

SAR and characterization of non-substrate isoindoline urea inhibitors of nicotinamide phosphoribosyltransferase (NAMPT).

Herein we disclose SAR studies that led to a series of isoindoline ureas which we recently reported were first-in-class, non-substrate nicotinamide phosphoribosyltransferase (NAMPT) inhibitors. Modification of the isoindoline and/or the terminal functionality of screening hit 5 provided inhibitors such as 52 and 58 with nanomolar antiproliferative activity and preclinical pharmacokinetics properties which enabled potent antitumor activity when dosed orally in mouse xenograft models. X-ray crystal structures of two inhibitors bound in the NAMPT active-site are discussed.

SAR of amino pyrrolidines as potent and novel protein-protein interaction inhibitors of the PRC2 complex through EED binding.

Herein we disclose SAR studies of a series of dimethylamino pyrrolidines which we recently reported as novel inhibitors of the PRC2 complex through disruption of EED/H3K27me3 binding. Modification of the indole and benzyl moieties of screening hit 1 provided analogs with substantially improved binding and cellular activities. This work culminated in the identification of compound 2, our nanomolar proof-of-concept (PoC) inhibitor which provided on-target tumor growth inhibition in a mouse xenograft model.

The EED protein-protein interaction inhibitor A-395 inactivates the PRC2 complex.

Polycomb repressive complex 2 (PRC2) is a regulator of epigenetic states required for development and homeostasis. PRC2 trimethylates histone H3 at lysine 27 (H3K27me3), which leads to gene silencing, and is dysregulated in many cancers. The embryonic ectoderm development (EED) protein is an essential subunit of PRC2 that has both a scaffolding function and an H3K27me3-binding function.

The SUV4-20 inhibitor A-196 verifies a role for epigenetics in genomic integrity.

Protein lysine methyltransferases (PKMTs) regulate diverse physiological processes including transcription and the maintenance of genomic integrity. Genetic studies suggest that the PKMTs SUV420H1 and SUV420H2 facilitate proficient nonhomologous end-joining (NHEJ)-directed DNA repair by catalyzing the di- and trimethylation (me2 and me3, respectively) of lysine 20 on histone 4 (H4K20). Here we report the identification of A-196, a potent and selective inhibitor of SUV420H1 and SUV420H2.

Discovery and Optimization of a Novel Triazole Series of GPR142 Agonists for the Treatment of Type 2 Diabetes.

GPR142 has been identified as a potential glucose-stimulated insulin secretion (GSIS) target for the treatment of type 2 diabetes mellitus (T2DM). A class of triazole GPR142 agonists was discovered through a high throughput screen. The lead compound suffered from poor metabolic stability and poor solubility.

The Histone Methyltransferase Inhibitor A-366 Uncovers a Role for G9a/GLP in the Epigenetics of Leukemia.

Histone methyltransferases are epigenetic regulators that modify key lysine and arginine residues on histones and are believed to play an important role in cancer development and maintenance. These epigenetic modifications are potentially reversible and as a result this class of enzymes has drawn great interest as potential therapeutic targets of small molecule inhibitors. Previous studies have suggested that the histone lysine methyltransferase G9a (EHMT2) is required to perpetuate malignant phenotypes through multiple mechanisms in a variety of cancer types.

Discovery of A-893, A New Cell-Active Benzoxazinone Inhibitor of Lysine Methyltransferase SMYD2.

A lack of useful small molecule tools has precluded thorough interrogation of the biological function of SMYD2, a lysine methyltransferase with known tumor-suppressor substrates. Systematic exploration of the structure-activity relationships of a previously known benzoxazinone compound led to the synthesis of A-893, a potent and selective SMYD2 inhibitor (IC50: 2.8 nM).

Target (In)Validation: A Critical, Sometimes Unheralded, Role of Modern Medicinal Chemistry.

Small molecule drug discovery commonly ventures into previously unknown and unexplored target space. For such programs, an important role of medicinal chemistry is to generate molecules that enable the most reliable conclusions from a preclinical target validation/invalidation study. Multiple facets of chemistry that provide the most rigorous results for such an experiment are highlighted.

Discovery and development of potent and selective inhibitors of histone methyltransferase g9a.

G9a is a histone lysine methyltransferase responsible for the methylation of histone H3 lysine 9. The discovery of A-366 arose from a unique diversity screening hit, which was optimized by incorporation of a propyl-pyrrolidine subunit to occupy the enzyme lysine channel. A-366 is a potent inhibitor of G9a (IC50: 3.

2-(4-Carbonylphenyl)benzoxazole inhibitors of CETP: attenuation of hERG binding and improved HDLc-raising efficacy.

The development of 2-phenylbenzoxazoles as inhibitors of cholesteryl ester transfer protein (CETP) is described. Efforts focused on finding suitable replacements for the central piperidine with the aim of reducing hERG binding: a main liability of our benchmark benzoxazole (1a). Replacement of the piperidine with a cyclohexyl group successfully attenuated hERG binding, but was accompanied by reduced in vivo efficacy.

2-(4-carbonylphenyl)benzoxazole inhibitors of CETP: scaffold design and advancement in HDLc-raising efficacy.

The development of 2-phenylbenzoxazoles as inhibitors of cholesteryl ester transfer protein (CETP) is described. Initial efforts aimed at engineering replacements for the aniline substructures in the benchmark molecule. Reversing the connectivity of the central aniline lead to a new class of 2-(4-carbonylphenyl)benzoxazoles.

Cross-coupling reactions of alkenylsilanolates. Investigation of the mechanism and identification of key intermediates through kinetic analysis.

The mechanism of the fluoride-free, palladium-catalyzed cross-coupling reaction of potassium (E)-heptenyldimethylsilanolate, K(+)(E)-1(-), with 2-iodothiophene has been investigated through kinetic analysis. The order of each component was determined by plotting the initial rates of the reaction against concentration. These data provided a mechanistic picture which involves a fast and irreversible oxidative insertion of palladium into the aryl iodide and a subsequent intramolecular transmetalation step from a complex containing a silicon-oxygen-palladium linkage.

Fluoride-promoted cross-coupling reactions of alkenylsilanols. Elucidation of the mechanism through spectroscopic and kinetic analysis.

The mechanism of the palladium-catalyzed cross-coupling reaction of (E)-dimethyl-(1-heptenyl)silanol ((E)-1) and of (E)-diisopropyl-(1-heptenyl)silanol ((E)-2) with 2-iodothiophene has been investigated through spectroscopic and kinetic analysis. A common intermediate in cross-coupling reactions of several types of organosilicon precursors has been identified as a hydrogen-bonded complex between tetrabutylammonium fluoride (TBAF) and a silanol. The order in each component has been determined by plotting the initial rates of the cross-coupling reaction at varying concentrations.

Cross-coupling reactions of organosilicon compounds: new concepts and recent advances.

This review highlights the rapid evolution of the newly-developed class of palladium-catalyzed cross-coupling reactions of organosilicon compounds. A myriad of heteroatom-containing silicon moieties (silyl hydrides, siletanes, silanols, silyl ethers, orthosiliconates, di- and polysiloxanes and pyridylsilanes) undergo mild and stereospecific cross-coupling. The diversity of methods for introduction of silicon groups into organic molecules and the range of organic electrophiles that can be used are emphasized.

Design and implementation of new, silicon-based, cross-coupling reactions: importance of silicon-oxygen bonds.

This Account chronicles the conceptual development, proof of principle, exploration of scope, and mechanistic investigations of a newly developed class of palladium-catalyzed cross-coupling reactions of silicon derivatives. Under the influence of fluoride activation a myriad of oxygen-containing silicon moieties undergo mild and stereospecific cross-coupling. The diversity of methods for introduction of silicon groupings into organic molecules and the range of organic electrophiles that can be used are outlined.

Cross-coupling reactions of alkenylsilanols with fluoroalkylsulfonates.

[reaction: see text] The design and development of an effective protocol for the palladium-catalyzed cross-coupling of (E)- and (Z)-heptenyldimethylsilanols with organo-triflates and nonaflates is described. Optimization of this coupling focused on the issues of both reactivity and stability of the psuedohalides in the presence of the nucleophilic fluoride promoter for the coupling. The crucial role of varying amounts of water to modulate the reactivity of the fluoride ion is highlighted.