Current opinion in drug discovery & development最新文献

This review highlights progress made during the past 2 to 3 years in the field of therapeutic locked nucleos(t)ides. Synthetic strategies to construct the conformationally locked nucleos(t)ides, their properties and potential therapeutic applications as antiviral compounds, and modified oligonucleotides to modulate antisense and RNAi properties are described.

Efficient routes for the creation of heterocycles continue to be one of the primary goals for solid-phase synthesis. Recent advances in this field rely most notably on transition-metal-catalysis and N-acyliminium chemistry to mediate a range of cyclization processes for the generation of compounds with significant structural complexity and diversity. This review describes some of the most systematic solid-phase approaches that are potentially suited for pharmaceutical applications, that is, the methods described are useful for the synthesis of compound collections, and exhibit tunable stereochemistry, scaffold structure, and appendage modification.

The past decade has witnessed the emergence of potassium organotrifluoroborates as a new class of nucleophilic boron reagents for Suzuki-Miyaura cross-coupling and Rh-catalyzed addition reactions. Potassium organotrifluoroborates are easily prepared, and most are indefinitely stable to air and moisture. Recent advances have focused on the utility of alkyltrifluoroborates in appending alkyl groups selectively and conveniently onto appropriate molecular substructures. This review describes strategies employing these reagents as nucleophilic substrates.

Efforts made by chemists to develop more sustainable processes have resulted in a large increase in greener technologies. Because solvents comprise greater than 80% by mass of a pharmaceutical batch process, the incorporation of solvent-free reactions is expected to significantly reduce the quantity of hazardous waste that is generated during these processes. This review highlights a diverse set of solvent-free organic reactions that can be employed in the development of various pharmaceutical drugs.

The asymmetric construction of optically active amine compounds is of paramount interest for the chemical industry and academic research. This review describes the use of catalytic asymmetric transformations, such as Mannich-type, Michael, cycloaddition and transfer-hydrogenation reactions using small organic molecules (eg, amino acids, secondary amines, peptides, thioureas and phosphoric acids) as catalysts, for the construction of important compounds for medicinal chemistry that exhibit anticancer, antibiotic or antiviral activity.

At the turn of the millennium, the DNA sequence encoding the histamine H4 receptor (H4R) was identified in data from human genome databases. Considering the clinical importance of H1R and H2R ligands, and the clinical trials that are ongoing for H3R ligands, the latest addition to the histamine receptor family was noted with interest by the pharmaceutical industry. Initial studies describing the expression of the H4R, and the activity of this receptor in (patho)physiology, suggested that the H4R played a role in the immune system. The introduction of the reference H4R antagonist JNJ-7777120 (Johnson & Johnson Pharmaceutical Research & Development LLC/Abbott Laboratories), and proof of the efficacy of this agent in models of asthma, allergic rhinitis and pruritus, highlighted the H4R as a novel drug target. The first clinical candidates targeting the H4R have been identified, and new H4R antagonists are expected to enter the clinic in the near future.

The mitochondria form dynamic organized networks or filaments that are controlled by fusion and fission events. A balance between mitochondrial fusion and fission is crucial for the correct function of these organelles. Thus, a detailed characterization of the proteins involved in mitochondrial fusion and fission, and the study of the mechanisms that regulate these two processes, would contribute to elucidating how this balance is achieved. In this regard, alterations in some of the proteins that participate in mitochondrial dynamics are linked to human pathology. In addition, experimental data support the view that mitochondrial metabolism is regulated via the manipulation of the proteins involved in mitochondrial dynamics, particularly the mitofusin 2 protein. This review evaluates the potential of mitochondrial fusion and fission proteins as targets for drug discovery, with an emphasis on mitofusin 2. The pharmacological modulation of mitochondrial dynamics may be beneficial for the treatment of specific disorders of mitochondrial dynamics and mitochondrial-inherited diseases, as well as in complex diseases with a central mitochondrial dysfunction.

The protein arginine deiminases (PADs), and in particular PAD4, have emerged as potential therapeutic targets for the treatment of rheumatoid arthritis (RA). In this review, evidence linking dysregulated PAD activity to the onset and progression of RA is presented, and the potential role of such aberrant activity in other human diseases, such as multiple sclerosis and cancer, is discussed. The known physiological roles of the PADs, particularly PAD4, and current knowledge regarding PAD structure, catalysis and inhibition are also described.