Direct oxidative C-H alkynylation of N-carbamoyl tetrahydroisoquinolines and dihydroisoquinolines.

An efficient oxidative C-H alkynylation of N-carbamoyl tetrahydroisoquinolines mediated by a TEMPO oxoammonium salt has been established. A variety of electronically varied N-carbamoyl tetrahydroisoquinolines reacted with a range of alkynyl potassium trifluoroborates smoothly under mild metal-free conditions. Dihydroisoquinolines were also suitable components for the reaction. The synthetic applicability of the method for facile access to structurally diverse bioactive molecules was further demonstrated.

Evaluation of WO2017098421: GSK's benzothiazine compounds as CD73 inhibitor filings.

INTRODUCTION: There are considerable interests in the development of novel small-molecule CD73 inhibitors for the treatment of cancers, autoimmune diseases, precancerous syndromes, and other diseases associated with CD73 activity. Areas covered: The application claims novel substituted benzothiadiazine derivatives as CD73 inhibitors for the treatment of cancer, precancerous syndromes, AIDS, autoimmune diseases, infections, atherosclerosis, and ischemia-reperfusion injury. Many of the exemplified compounds have pIC50 values between 5 to 8.4 against CD73. Expert Opinion: These benzothiadiazine derivatives provide good leads for the discovery of potent CD73 inhibitors for the treatment of cancer and other diseases mediated by adenosine and its action on adenosine receptors.

Recent advances in the discovery of potent and selective HDAC6 inhibitors.

Histone deacetylase HDAC6, a member of the class IIb HDAC family, is unique among HDAC enzymes in having two active catalytic domains, and has unique physiological function. In addition to the modification of histone, HDAC6 targets specific substrates including α-tubulin and HSP90, and are involved in protein trafficking and degradation, cell shape and migration. Selective HDAC6 inhibitors are an emerging class of pharmaceuticals due to the involvement of HDAC6 in different pathways related to neurodegenerative diseases, cancer, and immunology. Therefore, extensive investigations have been made in the discovery of selective HDAC6 inhibitors. Based on their different zinc binding groups (ZBGs), in this review, HDAC6 inhibitors are grouped as hydroxamic acids, a sulfur containing ZBG based derivatives and other ZBG-derived compounds, and their enzymatic inhibitory activity, selectivity and other biological activities are introduced and summarized.

Oxidative C-H functionalization of N-carbamoyl 1,2-dihydroquinolines.

A modular and efficient method for the synthesis of α-substituted 1,2-dihydroquinolines is described. Under mild metal-free conditions, readily available N-carbamoyl 1,2-dihydroquinolines undergo oxidative C-H alkynylation, alkenylation, and allylation with a range of potassium trifluoroborates using TEMPO oxoammonium salt as an oxidant.

Recent Research Advances in Selective Matrix Metalloproteinase-13 Inhibitors as Anti-Osteoarthritis Agents.

Matrix metalloproteinase-13 (MMP-13) plays a key role in the degradation of type II collagen in cartilage and bone in osteoarthritis (OA). The subtle differences between the S1' loop of MMP-13 and that of other MMPs offer a structural base for the design of selective MMP-13 inhibitors to mitigate the unperceived risk associated with inhibiting other MMP isoforms. In this review, we summarize zinc-binding and non-zinc-binding selective MMP-13 inhibitors. The zinc-binding MMP-13 inhibitors contain a small set of zinc-binding groups (ZBGs), including hydroxamic acid, pyrimidinetrione, reversed hydroxamic acid and hydantoin, carboxylic acid, 1,2,4,-triazole, and 1,2,4,-triazolone. The non-zinc-binding MMP-13 inhibitors have different structural scaffolds, including diphenyl ethers, biaryls (aryltetrazoliums, arylfurans, pyrazole-indoles), pyrimidines, and aryl/cycloalkyl-fused pyrimidines. This review provides a systematic overview of recent developments in MMP-13 inhibitors for the treatment of OA, with emphasis on their enzyme inhibitory potency, selectivity, and biological activities, and highlights the various binding modes of typical inhibitors with MMP-13.

Studies on pharmacokinetics and bioavailability of aminophylline in partridge chickens.

Veterinary medicine plays a significant role in the development of animal husbandry. Drugs residual in food would follow the food-chain coming into human body, which might bring hidden dangers to people. Chicken is the prime source of meat food, whose quality is important for our life and health. Therefore, it is necessary to realize the withdrawal period and establish an efficient, sensitive and accurate method for monitoring the metabolic process of drugs in chicken body. In this paper, the pharmacokinetics of aminophylline in partridge chicken after intravenous and oral administration was investigated using a sensitive high-performance liquid chromatography method. Plasma concentration-time profiles of aminophylline were analyzed by a non-compartmental model using Topfit 2.0. Following intravenous and oral administration, the peak concentrations (C max) were found to be (16.5 ± 3.0) µg/mL at (0.08 ± 0) h and (7.4 ± 1.5) µg/mL at (1.83 ± 1.11) h, respectively. The elimination half-time (t 1/2) after intravenous and oral administration were, respectively, (13.1 ± 4.17) h and (11.65 ± 1.14) h. Areas under the plasma concentration-time curve (AUC) were (209.6 ± 22.8) µg h mL(-1)(AUC0-t ) and (219.5 ± 28.3) µg h mL(-1) (AUC0→∞ ) after intravenous, and (165.1 ± 37.0) µg h mL(-1)(AUC0-t ) and (179.3 ± 35.6) µg h mL(-1) (AUC0→∞ ) after oral administration. Mean retention time (MRT) after intravenous and oral administration were, respectively, (14.06 ± 0.86) and (15.27 ± 0.62) h. The total clearance rates (CLtol) were (0.77 ± 0.10) mL min(-1) kg(-1) of intravenous and (0.97 ± 0.20) mL min(-1) kg(-1) of oral administration. The apparent distribution volume (V d) was (0.87 ± 0.27) and (0.97 ± 0.20) L kg(-1), respectively, for intravenous and oral administration. The absolute bioavailability (F) after oral administration was (83.1 ± 11.7) %. The results showed that aminophylline in partridge chickens had a longer elimination half-time, a smaller clearance rate, as well as a higher absolute bioavailability for oral administration. Therefore, aminophylline in partridge chickens produced a long healing efficacy and oral administration can achieve a good absorption which could meet the requirement.

Developments of DNA-dependent Protein Kinase Inhibitors as Anticancer Agents.

Repair of DNA double-strand breaks (DSBs) is critical for the maintenance of genome integrity, cell survival, and prevention tumorigenesis. Three pathways are responsible for the repair of DNA DSBs: homologous recombination (HR), single strand annealing (SSA) and non-homologous end joining (NHEJ). DNA-dependent Protein Kinase (DNA-PK), the key component of the NHEJ pathway, becomes an important target for cancer therapy. A large number of small molecules exhibit inhibitory activities against DNA-PK in an ATP-competitive manner. This paper reviews the recent developments of a diversity of small molecule DNA-PK inhibitors, with emphasis on their structural features, biological activities, and structure-activity relationships (SARs).

Developments of kinesin spindle protein inhibitors as antitumor agents based on the five-membered heterocycle scaffolds.

Kinesin spindle protein (KSP) plays an essential role in centrosome separation and formation of the bipolar mitotic spindle. Its exclusive involvement in the mitotic spindle of proliferating cells presents an opportunity for developing new anticancer agents with reduced side effects relative to antimitotics that target tubulin. Small molecule KSP inhibitors have demonstrated their potential as novel antimitotic agents. Several KSP inhibitors have progressed into clinical trials and many others are in preclinical developments. Recently, KSP inhibitors of wide structural diversity have appeared in literatures. This review will summarize the developments of KSP inhibitors based on the five-membered heterocycle scaffolds in recent 10 years. These small molecule KSP inhibitors were classified as dihydropyrazoles, dihydropyrroles, thiophenes, dihydrothiadiazoles, thiazoles and fused pyrroles, their structure-activity relationships were discussed.

Recent developments of small molecule PI3K/mTOR dual inhibitors.

The phosphoinositide 3-kinases (PI3Ks) are lipid kinases that play a central role in control of cell growth, proliferation, migration, survival and angiogenesis, and drive the progression of tumors by activating phosphoinositidedependent kinase, protein kinase B (Akt) and the mammalian target of rapamycin (mTOR). The PI3K/Akt/mTOR pathway has been shown to play an important role in cancer and has become an important target for anticancer drug development. An interest in targeting two important points along this critical signaling pathway has spurred the development of dual PI3K/mTOR inhibitors that could both prevent cancer cell proliferation and induce programmed cell death (apoptosis) by fully suppressing Akt activation. This review summarizes the developments of a diversity of small molecule dual PI3K/mTOR inhibitors in recent 10 years, with an emphasis on their structural features, the relevant biological activities, and the structure-activity relationships (SARs).

Recent developments of 19-nor-1,25-dihydroxyvitamin D3 analogues.

The vitamin D hormone, 1α,25-dihydroxyvitamin D3 [1,25-(OH)2 D3 ], exerts its hormonal effects predominantly on intestine, bone, and kidney, where it plays a crucial role in calcium and phosphorus homeostasis and bone mineralization. In addition to its classical actions, 1,25(OH)2 D3 exerts pleiotropic effects in a wide variety of target tissues and cell types, often in an autocrine/paracrine fashion. These biological activities of 1,25(OH)2 D3 have suggested a multitude of potential therapeutic applications for the vitamin D hormone in the treatment of hyperproliferative disorders (e.g. cancer and psoriasis), immune dysfunction (autoimmune diseases), and endocrine disorders (e.g. hyperparathyroidism). However, the calcemic effects induced by 1,25(OH)2 D3--hypercalcemia, increased bone resorption, and soft tissue calcification--limit the use of the natural ligand in these clinical applications. Therefore, numerous 1,25(OH)2 D3 analogues have been synthesized with the intent of producing therapeutic agents devoid of hypercalcemic and hyperphosphatemic side effects. To this aim, much attention has been focused on the development of 19-nor-vitamin D3 derivatives that lack the ring-A exocyclic methylene group (C19). In this review, the 19-nor-1,25(OH)2 D3 analogues are classified according to modifications made at the A-ring, the side chain, or both the A-ring and side chain, as well as other positions. The biological activities of these 19-nor-1,25(OH)2 D3 analogues are summarized and their structure-activity relationships and binding features with the vitamin D receptor (VDR) are discussed.

Pharmacokinetics of vertilmicin, a novel aminoglycoside antibiotic, in rats and dogs.

The pharmacokinetics of vertilmicin was investigated in rats and dogs following intramuscular or intravenous administration of vertilmicin. Following a single administration of an intramuscular dose, serum concentrations of vertilmicin peaked at 0.63 h in rats and 0.58 h in dogs. In rats, after intravenous administration of vertilmicin at dosages of 10, 20, and 40 mg/kg, the t1/2 values for vertilmicin were 0.81, 0.76, and 0.86 h, respectively, while after intramuscular administration of vertilmicin at dose of 20 mg/kg, the t1/2 value for vertiImicin was 0.79 h. In dogs, after intravenous or intramuscular administration of vertilmicin at a dose of 10 mg/kg, the t1/2 values for vertilmicin were 0.83 and 0.85 h, respectively. After intravenous dosing to rats vertilmicin was distributed to most organs and tissues, and kidney tissue exhibited the highest exposure, while the tissue with the lowest exposure was the brain. Following single intravenous administration of vertilmicin at a dose of 20 mg/kg to rats, about 81.1% of the vertilmicin was excreted in urine, while only 3.12 and 1.44% of the administered dose was excreted in feces and bile within 48 h. The mean values for the plasma protein binding of vertilmicin were 22.7 and 20.4% in rats and dogs, respectively. These results indicate that vertilmicin was rapidly absorbed and widely distributed into various tissues in rats. The pharmacokinetic behavior of vertilmicin was dose-dependent when increasing doses of vertilmicin were administered intravenously to rats. Renal excretion was the primary elimination route of vertilmicin following intravenous administration to rats.

The effects of salvianolic acid B from radix salvia miltiorrhizae on the oral pharmacokinetics of metoprolol and metoprolol acid in rats.

The present study aimed to investigate the effects of salvianolic acid B (SalB) isolated from Radix Salvia miltiorrhizae on the oral pharmacokinetics of metoprolol (MET) and metoprolol acid (META) in rats. The pharmacokinetic parameters of MET and META were measured after oral (15 mg/kg) administration of MET in rats in the presence and absence of SalB. Compared to the control given MET alone, with the concurrent administration of SalB (50 mg/kg), the AUC and C(max) of MET increased by 51.7% and 27.7%, and the AUC and C(max) of META decreased by 26.5% and 19.6%, respectively. With the presence of SalB, the metabolic ratio was markedly decreased by 50.8%. However, no significant changes were observed in the pharmacokinetic parameters of SalB when it was combined with MET.