Type 2 diabetes mellitus (DM) is a complex chronic disorder and a major global health problem. Insulin resistance is the primary detectable abnormality and the main characteristic feature in individuals with type 2 DM. Protein tyrosine phosphatase 1B (PTP1B) is a key negative regulator of the insulin signaling pathway, which dephosphorylates insulin receptor and insulin receptor substrates, suppressing the insulin signaling cascade. Therefore, the inhibition of PTP1B has become a potential strategy in the management of type 2 DM. In this study, a library of 22 pyrazoles was evaluated here for the first time against human PTP1B activity, using a microanalysis screening system. The results showed that 5-(2-hydroxyphenyl)-3-{2-[3-(4-nitrophenyl)-1,2,3,4-tetrahydronaphthyl]}-1-phenylpyrazole 20 and 3-(2-hydroxyphenyl)-5-{2-[3-(4-methoxyphenyl)]naphthyl}pyrazole 22 excelled as the most potent inhibitors of PTP1B, through noncompetitive inhibition mechanism. These findings suggest that the presence of additional benzene rings as functional groups in the pyrazole moiety increases the ability of pyrazoles to inhibit PTP1B. The most active compounds showed selectivity over the homologous T-cell protein tyrosine phosphatase (TCPTP). Molecular docking analyses were performed and revealed a particular contact signature involving residues like TYR46, ASP48, PHE182, TYR46, ALA217 and ILE219. This study represents a significant beginning for the design of novel PTP1B inhibitors.

Synthetic inhibitors and organic amendment have been proposed for mitigating greenhouse gas N2O emissions. However, their combined effect on the N2O emissions and ammonia-oxidizer (ammonia-oxidizing bacteria and archaea, AOB and AOA) communities remains unclear in calcareous soils under climate warming. We conducted two incubation experiments (25 and 35 °C) to examine how N2O emissions and AOA and AOB communities responded to organic amendment (urea plus cattle manure, UCM), and in combination with urease (N-(n-butyl) thiophosphoric triamide, NBPT) and nitrification inhibitor (nitrapyrin). The treatments of UCM + nitrapyrin and UCM + nitrapyrin + NBPT significantly lowered total N2O emissions by average 64.5 and 71.05% at 25 and 35 °C, respectively, compared with UCM treatment. AOB gene abundance and α-diversity (Chao1 and Shannon indices) were significantly increased by the application of urea and manure (P < 0.05). However, relative to UCM treatment, nitrapyrin addition treatments decreased AOB gene abundance and Chao 1 index by average 115.4 and 30.4% at 25 and 35 °C, respectively. PCA analysis showed that UCM or UCM plus nitrapyrin notably shifted AOB structure at both temperatures. However, fertilization had little effects on AOA community (P > 0.05). Potential nitrification rate (PNR) was greatly decreased by nitrapyrin addition, and PNR significantly positively correlated with AOB gene abundance (P = 0.0179 at 25 °C and P = 0.0029 at 35 °C) rather than AOA (P > 0.05). Structural equation model analysis showed that temperature directly increased AOA abundance but decrease AOB abundance, while fertilization indirectly influenced AOB community by altering soil NH4+, pH and SOC. In conclusion, the combined application of organic amendment, NBPT and nitrapyrin significantly lowered N2O emissions via reducing AOB community in calcareous soil even at high temperature. Our findings provide a solid theoretical basis in mitigating N2O emissions from calcareous soil under climate warming.

Matrix metalloproteinases are enzymes that degrade the extracellular matrix. They have different substrates but similar structural organization. Matrix metalloproteinases are involved in many physiological and pathological processes and there is a need to develop inhibitors for these enzymes in order to modulate the degradation of the extracellular matrix (ECM). There exist two classes of inhibitors: endogenous and synthetics. The development of synthetic inhibitors remains a great challenge due to the low selectivity and specificity, side effects in clinical trials, and instability. An extensive review of currently reported synthetic inhibitors and description of their properties is presented.

Introduction: Thrombosis is a common causal pathology for stroke, acute coronary syndrome and venous thromboembolism disorders, which are the leading cause of death worldwide. Anticoagulants have exhibited a crucial role in the prevention and treatment of thrombotic diseases. Factor Xa (FXa) is a serine protease with a central role in activating the complex blood coagulation cascade, and it is therefore regarded as an attractive target for antithrombotic agents. Areas covered: The authors review the current status of medicinal chemistry strategies for the discovery of novel FXa inhibitors and provide their expert perspectives on their future development. Expert opinion: Even if only a number of small-molecule FXa inhibitors have been reported to date, all currently available FXa inhibitors are associated with significant risk of bleeding, which may become life-threatening. There is, therefore, an urgent and unmet demand for potent novel FXa inhibitors that are potent treatments for thrombotic disorders, but which have a reduced risk of bleeding if their use is to be increasingly favored.

Matrix metalloproteinases (MMPs), A Disintegrin and Metalloproteinase (ADAM) and A Disintegrin and Metalloproteinase with Thrombospondin Motif (ADAMTS) are zinc-dependent endopeptidases that play a critical role in the destruction of extracellular matrix proteins and, the shedding of membrane-bound receptor molecules in various forms of arthritis and other diseases. Under normal conditions, MMP, ADAM and ADAMTS gene expression aids in the maintenance of homeostasis. However, in inflamed synovial joints characteristic of rheumatoid arthritis and osteoarthritis. MMP, ADAM and ADAMTS production is greatly increased under the influence of pro-inflammatory cytokines. Analyses based on medicinal chemistry strategies designed to directly inhibit the activity of MMPs have been largely unsuccessful when these MMP inhibitors were employed in animal models of rheumatoid arthritis and osteoarthritis. This is despite the fact that these MMP inhibitors were largely able to suppress pro-inflammatory cytokine-induced MMP production in vitro. A focus on ADAM and ADAMTS inhibitors has also been pursued. Thus, recent progress has identified the \"sheddase\" activity of ADAMs as a viable target and the development of GW280264X is an experimental ADAM17 inhibitor. Of note, a monoclonal antibody, GLPG1972, developed as an ADAMTS-5 inhibitor, entered a Phase I OA clinical trial. However, the failure of many of these previously developed inhibitors to move beyond the preclinical testing phase has required that novel strategies be developed that are designed to suppress both MMP, ADAM and ADAMTS production and activity.

Aldose reductase (ALR2) is both the key enzyme of the polyol pathway, whose activation under hyperglycemic conditions leads to the development of chronic diabetic complications, and the crucial promoter of inflammatory and cytotoxic conditions, even under a normoglycemic status. Accordingly, it represents an excellent drug target and a huge effort is being done to disclose novel compounds able to inhibit it.
This literature survey summarizes patents and patent applications published over the last 5 years and filed for natural, semi-synthetic and synthetic ALR2 inhibitors. Compounds described have been discussed and analyzed from both chemical and functional angles.
Several ALR2 inhibitors with a promising pre-clinical ability to address diabetic complications and inflammatory diseases are being developed during the observed timeframe. Natural compounds and plant extracts are the prevalent ones, thus confirming the use of phytopharmaceuticals as an increasingly pursued therapeutic trend also in the ALR2 inhibitors field. Intriguing hints may be taken from synthetic derivatives, the most significant ones being represented by the differential inhibitors ARDIs. Differently from classical ARIs, these compounds should fire up the therapeutic efficacy of the class while minimizing its side effects, thus overcoming the existing limits of this kind of inhibitors.

BACKGROUND: Tryptase is one of the main serine-proteinases located in the secretory granules of mast cells, and is released through degranulation, which is involved in the pathogenesis of allergic inflammatory disease, cardiovascular diseases, lung fibrosis and tumor. Therefore, inhibitors targeting tryptase may represent a new direction for the treatment of allergic inflammatory disease and other diseases. Areas covered: In this article, we discussed the history and development of tryptase inhibitors and described a variety of tryptase inhibitors via their structures and biological importance in clinical studies and drug development for tryptase-related diseases. Expert opinion: Initial tryptase inhibitors based on indole structure as the hydrophobic substituent on a benzylamine-piperidine template have low specificity and poor bioavailability. Therefore, designing new and specific inhibitors targeting tryptase should be involved in future clinical studies. Modifications toward indoles with varying N-substitution, introducing an amide bond, and growing the chain length contribute to an increase in the specific selectivity and potency of tryptase inhibitors. Tryptase has become the research hotspot to explore many related diseases. Therefore, there has been growing appreciation for the potential importance of the tryptase inhibitors as a target for treating these diseases.

Tyrosinase is responsible for melanin production. The overproduction of melanin causes many skin disorders. The inhibition of tyrosinase activity would appear to be the most rational and explicit way of overcoming these issues.
Thirty eight patents on synthetic tyrosinase inhibitors issued since 2011 were reviewed. Inhibitors were categorized by chemical structure and assigned to eight classes. Information on potent inhibitors in each class is provided.
Many tyrosinase inhibitors of natural or synthetic origin have been identified, but very few are qualified for clinical use. Thus medicinal scientists have to work more on the identification of potent and safe tyrosinase inhibitors. Various chemical scaffolds have been explored. Among them, the scaffolds such as resorcinol, biaryl, imidazolethione, β-phenyl-α,β-unsaturated carbonyl, and some double strand oligonucleotides have shown high tyrosinase inhibition, low toxicities, and great potencies. Detail structure activity relationship studies of these potential scaffolds could provide directions for a new and potent tyrosinase inhibitors. Furthermore new trends, such as the use of synergistic phenomena, salt formation, drug repositioning and designing of multi-targeted tyrosinase inhibitors could expand search areas for much improved tyrosinase inhibitors.