Efficient synthesis of dichlorodenafil, an unapproved sildenafil analogue appearing in non-prescription supplements.

We have developed an efficient synthesis of dichlorodenafil (4), an unapproved sildenafil analogue isolated from dietary supplements. Our sequence employs POCl(3)-mediated chlorination of readily available chloroacetyl compound 7 followed by selective hydrolysis of the chloro-heterocycle function. Our synthesis confirms the structure of the illegal additive, and will provide regulatory agencies with ready access to authentic standard samples of dichlorodenafil (4) to aid in their mission to protect the public from unapproved and potentially harmful erectile dysfunction (ED) drug analogues that are added to herbal and dietary supplements without providing users with appropriate toxicological or pharmacological information.

JP-1366: A novel and potent potassium-competitive acid blocker that is effective in the treatment of acid-related diseases.

The global prevalence of GERD is substantially increasing each year, and GERD is a chronic disease that reduces the quality of life of patients. The efficacy of conventional drugs is diverse, and most require long-term or lifetime administration; thus, the development of more effective therapeutic agents is needed. Herein, a more effective treatment for GERD was tested. We investigated whether JP-1366 affected gastric H+/K+-ATPase activity and used the Na+/K+-ATPase assay to confirm the selectivity of H+/K+-ATPase inhibition. To clarify the mechanism of enzyme inhibition, JP-1366 and TAK-438 were analyzed by Lineweaver-Burk. Also, we investigated the effects of JP-1366 in various models involving reflux esophagitis. We found that JP-1366 mediates strong, selective, and dose-dependent inhibition of H+/K+-ATPase. We found that JP-1366 significantly suppressed gastric acid secretion in histamine-treated pylorus-ligated rats in a dose-dependent manner. Additionally, we confirmed that JP-1366 inhibited histamine-stimulated gastric acid secretion in the HPD model. JP-1366 exhibited a more than 2-fold higher inhibitory effect on esophageal injury than TAK-438 in GERD lesions and had a more potent inhibitory effect in indomethacin- or aspirin-induced gastric ulcer rat models than TAK-438. Additionally, JP-1366 inhibited gastric ulcers. These results support the possibility that JP-1366 is a good candidate drug for treating acid-related diseases.

Novel thiophenyl C-aryl glucoside SGLT2 inhibitors as potential antidiabetic agents.

Novel thiophene C-aryl glucoside SGLT2 inhibitors were designed and synthesized. Two different types of thiophene derivatives were readily prepared. Among the compounds tested, ethylphenyl at the distal ring 71p showed the best in vitro inhibitory activity in this series to date (IC(50)=4.47 nM) against SGLT2.

Pyrimidinylmethylphenyl glucoside as novel C-aryl glucoside SGLT2 inhibitors.

Novel C-aryl glucoside SGLT2 inhibitors containing pyrimidine motif were designed and synthesized for biological evaluation. Among the compounds assayed, pyrimidine containing methylthio moiety 11 g demonstrated the best in vitro inhibitory activity against SGLT2 in this series to date (IC(50)=10.7 nM).

Arylpiperazine-containing pyrimidine 4-carboxamide derivatives targeting serotonin 5-HT(2A), 5-HT(2C), and the serotonin transporter as a potential antidepressant.

Pyrimidine usually has good pharmacokinetic properties as a drug substance and considerable efforts have been devoted to develop pyrimidine derivatives into drug candidates. Arylpiperazine-containing pyrimidine 4-carboxamide derivatives were synthesized and evaluated for binding to serotonin receptors and transporter. Pyrimidine derivatives showed good antidepressant activity in FST (forced swimming test) animal model and also displayed no appreciable inhibitory activity against hERG channel blocking assay. Herein SAR studies of pyrimidine derivatives targeting serotonin receptors and transporter will be disclosed.

Diarylimidazolyl oxadiazole and thiadiazole derivatives as cannabinoid CB1 receptor antagonists.

Since the CB1 receptor antagonist SR141716 (rimonabant) was reported to modulate food intake, CB1 antagonism has been considered as a new therapeutic target in the treatment of obesity. Several series of derivatives based on diarylimidazolyl oxadiazole and thiadiazole scaffolds were synthesized and tested for CB1 receptor binding affinity. SAR studies directed toward the optimization of imidazole scaffolds resulted in the discovery of 10s which showed highest potency for CB1 receptor binding affinity (IC(50)=1.91nM) prepared to date.

Substituted pyrimidines as cannabinoid CB1 receptor ligands.

Cannabinoid CB1 receptors have been the avenue of extensive studies since the first clinical results of rimonabant (SR141716) for the treatment of obesity and obesity-related metabolic disorders were reported in 2001. To further evaluate the properties of CB receptors, we have designed and efficiently prepared a series of substituted pyrimidines based on chemical structure of Merck's taranabant, a cannabinoid CB1 receptor inverse agonist. Noticeably, N4-((2S,3S)-3-(3-bromophenyl)-4-(4-chlorophenyl)butan-2-yl)-N6-butylpyrimidine-4,6-diamine (13b) demonstrated good binding affinity and decent selectivity for CB1 receptor (IC(50)=16.3nM, CB2/CB1=181.6).

Design, synthesis and biological evaluation of piperazine analogues as CB1 cannabinoid receptor ligands.

After the CB1 receptor antagonist SR141716 (rimonabant) was previously reported to modulate food intake, CB1 antagonism has been considered as a new therapeutic target for the treatment of obesity. Several series of urea, carbamate, amide, sulfonamide and oxalamide derivatives based on 1-benzhydrylpiperazine scaffold were synthesized and tested for CB1 receptor binding affinity. The SAR studies to optimize the CB1 binding affinity led to the potent urea derivatives. After the additional SAR studies to optimize the substituents of diphenyl rings, the combination of 2-chlorophenyl and 4-chlorophenyl turned out to be the most potent scaffold. The CB2 binding affinity assay as well as functional assay was also conducted on these compounds. Herein we wish to introduce several novel CB1 antagonists with IC(50) values less than 100 nM for the CB1 receptor binding.

Construction of 6,10-syn- and -anti-2,5-Dioxabicyclo[2.2.1]heptane Skeletons via Oxonium Ion Formation/Fragmentation: Prediction of Structure of (E)-Ocellenyne by NMR Calculation.

A highly efficient and stereoselective route to potential synthetic intermediates for ocellenyne and related C15 acetogenin natural products with 6,10-syn- and 6,10-anti-2,5-dioxabicyclo[2.2.1]heptane core structures has been developed by means of an iterative biogenesis-inspired oxonium ion formation/fragmentation sequence. In accordance with chemical transformations, the most likely stereostructure for (E)-ocellenyne on the basis of GIAO 13C NMR calculations possesses a 6,10-anti-2,5-dioxabicyclo[2.2.1]heptane core, as predicted from a plausible biosynthetic pathway, instead of the spectroscopically proposed 6,10-syn-2,5-dioxabicyclo[2.2.1]heptane skeleton.

Arthroscopic Assessment of Intra-Articular Lesion after Surgery for Rotational Ankle Fracture.

BACKGROUND: The purpose of this study was to report findings of exploratory arthroscopic assessment performed in conjunction with removal of internal fixation device placed in the initial surgery for rotational ankle fracture. METHODS: A total of 53 patients (33 male, 20 female) who underwent surgery for rotational ankle fracture between November 2002 and February 2008 were retrospectively reviewed. All patients gave consent to the exploratory arthroscopic surgery for the removal of internal fixation devices placed in the initial surgery. Lauge-Hansen classification system of ankle fractures was assessed for all patients. Intra-articular lesions (osteochondral lesion, loose body, and fibrosis) were evaluated via ankle arthroscopy. Comparative analysis was then performed between radiological classification of ankle fracture/patient's symptoms and arthroscopic findings. RESULTS: Lauge-Hansen classification system of ankle fractures included supination-external rotation type (n = 35), pronation-external rotation type (n = 9), and pronation-abduction type (n = 9). A total of 33 patients exhibited symptoms of pain or discomfort while walking whereas 20 exhibited no symptoms. Arthroscopic findings included abnormal findings around the syndesmosis area (n = 35), intra-articular fibrosis (n = 51), osteochondral lesions of the talus (n = 33), loose bodies (n = 6), synovitis (n = 13), and anterior bony impingement syndrome (n = 3). Intra-articular fibrosis was seen in 31 of symptomatic patients (93.9%). Pain or discomfort with activity caused by soft tissue impingement with meniscus-like intra-articular fibrosis were found in 19 patients. There was statistical significance (p = 0.02) between symptoms (pain and discomfort) and the findings of meniscus-like fibrosis compared to the group without any symptom. CONCLUSIONS: Arthroscopic examination combined with treatment of intra-articular fibrosis arising from ankle fracture surgery may help improve surgical outcomes.

The effect of autotransfusion system in minimally invasive total knee arthroplasty.

PURPOSE: To evaluate the effect of autotransfusion system in minimally invasive total knee arthroplasty (TKA). MATERIALS AND METHODS: Seventy-one patients who underwent unilateral minimally invasive TKA between October 2009 and June 2010 were selected. The first group included 36 patients who received standard vacuum drainage and the second group, 35 patients who underwent autologous retransfusion drainage. In the first group, allogeneic blood transfusion was performed if the postoperative hemoglobin level was <7.0 g/dL or 7.0-8.0 g/dL with the presence of a medical complication and an anemic symptom. The second group received autotransfusion and allogeneic transfusion additionally according to the same criteria. Changes in the pre- and postoperative hemoglobin level, amount of auto- or allotransfusion, and frequency of allogeneic transfusion were assessed. RESULTS: Allogeneic transfusion was required in 13 patients (36.1%) in the first group and four patients (11.4%) in the second group. The mean allogeneic transfusion volume was significantly low in the second group compared to the first group (64.4 mL vs. 278.9 mL; p<0.05). The hemoglobin level on the 1st postoperative day compared to the preoperative level decreased by 22.6% in the first group and 11.7% in the second group. The postoperative hemoglobin level was higher in the second group (p<0.05). CONCLUSIONS: Minimally invasive unilateral TKA with an autotransfusion system can be beneficial in patients with no medical complications because of the decreased allogeneic transfusion.

Concise synthesis of dimemorfan (DF) starting from 3-hydroxymorphinan (3-HM).

Dimemorfan (DF) has been known to possess neuroprotective properties. While this promising compound deserves further biological evaluation, synthetic methods have not improved since Murakami group unveiled the synthetic efforts in 1972. Herein a succinct synthesis toward DF from commercially available 3-hydroxymorphinan (3-HM) is disclosed. Other morphinan analogs have been effectively prepared by adopting the similar methodology.