Synthesis and biological evaluation of N-(3-fluorobenzyl)-4-(1-(methyl-d3)-1H-indazol-5-yl)-5-(6-methylpyridin-2-yl)-1H-imidazol-2-amine as a novel, potent ALK5 receptor inhibitor.

Specific inhibition of ALK5 provides a novel method for controlling the development of cancers and fibrotic diseases. In this work, a novel series of N-(3-fluorobenzyl)-4-(1-(methyl-d3)-1H-indazol-5-yl)-5-(6-methylpyridin-2-yl)-1H-imidazol-2-amine (11), a potential clinical candidate, was synthesized by strategic incorporation of deuterium at potential metabolic soft spots and identified as ALK5 inhibitors. This compound has a low potential for CYP-mediated drug-drug interactions as a CYP450 inhibitor (IC50 = >10 µM) and showed potent inhibitory effects in cellular assay (IC50 = 3.5 ± 0.4 nM). The pharmacokinetic evaluation of 11 in mice demonstrated moderate clearance (29.0 mL/min/kg) and also revealed high oral bioavailability in mice (F = 67.6%).

Evaluation of a screw insertion landmark for a minimally invasive repair technique in induced bilateral sacroiliac luxation in feline cadavers.

OBJECTIVES: The aim of this study was to describe an alternative landmark for screw insertion into the body of the ilium with bilateral sacroiliac luxation in cats. METHODS: Seven cat cadavers with artificially induced bilateral sacroiliac luxation were used. The screw insertion point was determined using the caudal iliac crest and cranial acetabular rim. These two points make the first guideline; a second guideline ran perpendicular to the caudal iliac crest point. The screw insertion point was halfway along the second guideline across the ilium body. Surgery was performed in a minimally invasive manner using fluoroscopy. RESULTS: Postoperative radiographs and CT were performed. In the postoperative evaluation, the sacroiliac joint reduction percentage was almost 90% and there was no significant difference in pelvic canal diameter ratio before and after surgery. Screw depth/sacral width was >60% in all cadavers. On CT, the angle between the screw and sacrum wing was within the normal range of 96.24° to the left and 98.65° to the right, except in one case. CONCLUSIONS AND RELEVANCE: In previous studies, surgical repair was based on having an intact contralateral ilium. However, this method is not applicable to patients with bilateral sacroiliac luxation and is mostly performed using open reduction methods. The screw insertion point suggested in this study offers a potential alternative repair technique for patients with bilateral sacroiliac luxation.

IDMap: facilitating the detection of potential leads with therapeutic targets.

UNLABELLED: Pharmaceutical industry has been striving to reduce the costs of drug development and increase productivity. Among the many different attempts, drug repositioning (retargeting existing drugs) comes into the spotlight because of its financial efficiency. We introduce IDMap which predicts novel relationships between targets and chemicals and thus is capable of repositioning the marketed drugs by using text mining and chemical structure information. Also capable of mapping commercial chemicals to possible drug targets and vice versa, IDMap creates convenient environments for identifying the potential lead and its targets, especially in the field of drug repositioning. AVAILABILITY: IDMap executable and its user manual including color images are freely available to non-commercial users at http://www.equispharm.com/idmap

Flavonoids as mushroom tyrosinase inhibitors: a fluorescence quenching study.

Flavonoids, a group of naturally occurring antioxidants and metal chelators, can be used as tyrosinase inhibitors due to their formation of copper-flavonoid complexes. Thus, to investigate the underlying inhibition mechanism, a large group of flavonoids from several major flavones and flavonols were tested using fluorescence quenching spectroscopy. In addition, large differences in the tyrosinase inhibitory activities and chelating capacities according to the location of the hydroxyl group(s) in combination with the A and B rings in the flavonoids were confirmed. Accordingly, the major conclusions from this work are as follows: (i) The tyrosinase inhibitory activity is not only dependent on the number of hydroxyl groups in the flavonoids, (ii) the enzyme is primarily quenched by the hydroxyl group(s) of A and B rings on the ether side of the flavonoids, and (iii) the tyrosinase inhibitory activity of 7,8,3',4'-tetrahydroxyflavone is supported by a virtual model of docking with the mushroom tyrosinase, which depicts the quenching of the enzyme. The results also demonstrated that the dihydroxy substitutions in the A and B rings are crucial for Cu2+-chelate formation, thereby influencing the tyrosinase inhibitory activity.