Rational design of inhibitors of the bacterial cell wall synthetic enzyme GlmU using virtual screening and lead-hopping.

An aminoquinazoline series targeting the essential bacterial enzyme GlmU (uridyltransferase) were previously reported (Biochem. J.2012, 446, 405). In this study, we further explored SAR through a combination of traditional medicinal chemistry and structure-based drug design, resulting in a novel scaffold (benzamide) with selectivity against protein kinases. Virtual screening identified fragments that could be fused into the core scaffold, exploiting additional binding interactions and thus improving potency. These efforts resulted in a hybrid compound with target potency increased by a 1000-fold, while maintaining selectivity against selected protein kinases and an improved level of solubility and protein binding. Despite these significant improvements no significant antibacterial activity was yet observed within this class.

New implant technique for separation of the seminal vesicle and rectal mucosa for high-dose-rate prostate brachytherapy.

PURPOSE: For safer treatment of seminal vesicles (SVs), we initiated a new technique using an anchor applicator for high-dose-rate interstitial brachytherapy (HDR-ISBT) of prostate cancer. METHODS AND MATERIALS: Between January 2004 and March 2005, 23 intermediate- to high-risk patients were treated with HDR-ISBT as monotherapy. Transrectal ultrasonography guided implantation of the treatment applicator in and around the prostate gland and proximal SV. We used an "anchor" applicator to prevent posterior displacement of the SV. After insertion of the anchor applicator, the actual treatment applicator was implanted at the best position for optimal SV coverage. SV coverage was analyzed using a dose-volume histogram. RESULTS: Implantation of the applicator on the posterior side of the SV was successful for 43 of 46 SVs (93%). The median percentage of the SVs receiving the prescribed dose was 41% (range 11-86%). Only one case of acute Grade 2 toxicity (3%) was seen. CONCLUSIONS: Our anchor applicator technique for HDR-ISBT can separate the SV from the rectum. This is the first report of dose-volume histogram analysis of the SV for HDR-ISBT.

New ambulatory implant technique of high-dose-rate interstitial brachytherapy for prostate cancer.

PURPOSE: The aim of this study was to improve the performance status of prostate cancer patients during high-dose-rate interstitial brachytherapy (HDR-ISBT). To this end, we have developed a new ambulatory implant technique. MATERIALS AND METHODS: Ten prostate cancer patients were treated with HDR-ISBT as monotherapy from October 2003 until March 2004. We utilized a new removable template, a flexible applicator with a nonmetallic bead and button stopper, and an inner catheter connecting the applicator and the transfer tube of the brachytherapy unit. We shortened the connector end of the flexible applicator to enable the patient to sit down and walk freely during the treatment time. RESULTS: All 10 patients could walk without any support. No problem in the application was observed. CONCLUSION: Our new ambulatory implant technique for HDR-ISBT was able to improve the performance status of prostate cancer patients.

Design, synthesis, and structure-activity relationships of potent GPIIb/IIIa antagonists: discovery of FK419.

The discovery of the non-peptide antiplatelet injectable agent FK419 is reported. Based on the beta-turn structure of RGD peptide sequences in the alpha chain of fibrinogen, which binds the glycoprotein IIb/IIIa (GPIIb/IIIa) on the surface of platelets to induce platelet aggregation, the prototype 2 was designed. After further substituent effects were investigated at the alpha-position of the carboxylic acid in 2, we enhanced platelet aggregation inhibition, and discovered the useful feature of reduced prolongation of bleeding time. Finally, the potent platelet aggregation inhibitor FK419 (3) could be discovered. FK419 shows a safe feature of reduced prolongation of bleeding time, as well as potent inhibition of platelet aggregation.

Synthesis and antibacterial evaluation of novel 2-[N-Imidoylpyrrolidinyl] carbapenems.

The synthesis, antibacterial activity and DHP-susceptibility of a series of novel carbapenems, directly linked with heterocyclic moiety are described. Especially, the compounds linked pyrrolidine-carbapenem exhibited to have a good antibacterial activity against Staphylococcus aureus (MRSA) as well as Pseudomonas aeruginosa to maintain a good stability towards DHP-I.

Pharmacological characterization of FR194921, a new potent, selective, and orally active antagonist for central adenosine A1 receptors.

Adenosine A1 receptors in the brain are believed to play an important role in brain functioning. We have discovered a novel adenosine A1 receptor antagonist, FR194921 (2-(1-methyl-4-piperidinyl)-6-(2-phenylpyrazolo[1,5-a]pyridin-3-yl)-3(2H)-pyridazinone), and characterized the pharmacological activity in the present study. FR194921 showed potent and selective affinity for the adenosine A1 receptor without affinity for A2A and A3 receptors and did not show any species differences in binding affinity profile among human, rat, and mouse. Pharmacokinetic study in rats revealed that FR194921 was orally active and highly brain penetrable. Oral administration of FR194921 dose-dependently ameliorated the hypolocomotion induced by the A1 receptor agonist N6-cyclopentyladenosine in rats, indicating this compound exerts A1-antagonistic action in vivo. In the passive avoidance test, scopolamine (1 mg/kg)-induced memory deficits were significantly ameliorated by FR194921 (0.32, 1 mg/kg). In two animal models of anxiety, the social interaction test and elevated plus maze, FR194921 showed specific anxiolytic activity without significantly influencing general behavior. In contrast, FR194921 did not show antidepressant activity even at a dose of 32 mg/kg in the rat forced swimming test. These results indicate that the novel, potent, and selective adenosine A1 receptor antagonist FR194921 exerts both cognitive-enhancing and anxiolytic activity, suggesting the therapeutic potential of this compound for dementia and anxiety disorders.