Discovery of Piperidine-Linked Pyridine Analogues as Potent Non-Nucleoside HIV-1 Reverse Transcriptase Inhibitors.

Discovery of Piperidine-Linked Pyridine Analogues as Potent Non-nucleoside HIV-1 Reverse Transcriptase Inhibitors.

ChemMedChem. 2013 May 3;
Chen X, Li Y, Ding S, Balzarini J, Pannecouque C, De Clercq E, Liu H, Liu X

In our continued efforts to discover more active and less toxic HIV-1 non-nucleoside reverse transcriptase inhibitors, we recently designed a novel series of piperidine-linked pyridine analogues on the basis of diarylpyrimidine derivatives, among which two drugs-etravirine and rilpivirine-are approved for use by the US FDA. The title compounds were evaluated for activity against wild-type and resistant mutant strains of HIV-1 as well as HIV-2 in MT-4 cells. The highly potent compound BD-c1 (EC50 =10?nM, CC50 ?146??M, SI?14?126) displays lower cytotoxicity and higher selectivity than etravirine (EC50 =2.2?nM, CC50 =28??M, SI=12?884) against wild-type HIV-1. Compound BD-e2 (EC50 =5.1?nM) shows greater antiviral efficacy against wild-type HIV-1 than do the four reference drugs nevirapine, delavirdine, efavirenz, and zidovudine. Many compounds were also found to be active against the frequently observed drug-resistant double mutant (K103N+Y181C) HIV-1 strain. Herein we report the design, synthesis, anti-HIV evaluation, preliminary structure-activity relationships, and molecular simulations of novel piperidine-linked pyridine analogues. HubMed – drug


New drug approval times and safety warnings in the United States and Canada, 1992-2011.

J Popul Ther Clin Pharmacol. 2013; 20(2): e67-81
B Rawson NS

BackgroundNew drug approvals in the US and Canada were reviewed in short-term studies in the 1990s. A database of drugs approved in both countries between 1992 and 2011 exists allowing for a longer time horizon to assess trends.ObjectiveTo compare review times of drugs approved in the US and Canada over the 20-year period and their duration on the respective markets until any serious safety risk arose.MethodsData on submission and approval dates and review type were obtained from the regulatory agencies.Results 454 drugs were approved in both countries in the 20-year period for which the US median approval time was shorter than the Canadian median by >6 months (382 versus 574 days). Nevertheless, in 2007-11, the median approval times were closer in the two countries (302 and 356 days, respectively). 3% of the drugs were discontinued for safety reasons in both countries. The 10-year survival rate without a serious safety warning was significantly lower in Canada (58.4%) than in the US (69.3%). Being approved in 2002-11 with a shorter review time had the greatest impact on a drug receiving a serious safety warning.ConclusionsOverall, new drug approval times in the two countries in the last five years were closer, although some important differences remain so that Canadians still wait longer for some new drugs to be approved. The survival rate of a drug without a serious warning decreased substantially in the last decade in both countries, especially in drugs approved with shorter review times. HubMed – drug


Aspirin desensitisation for Chinese patients with coronary artery disease.

Hong Kong Med J. 2013 May 6;
Lee JK, Tsui KL, Cheung CY, Chau CH, Chan HL, Wu KL, Cheung GS, Choi MC, Chan KK, Li SK

OBJECTIVE. To assess the efficacy and safety of aspirin desensitisation in Chinese patients with coronary artery disease. DESIGN. Case series. SETTING. A regional hospital in Hong Kong. PATIENTS. Chinese patients with coronary artery disease and a history of a hypersensitivity reaction to aspirin or non-steroidal anti-inflammatory drug, who underwent aspirin desensitisation between February 2008 and July 2012. RESULTS. There were 24 Chinese patients with coronary artery disease who were admitted to our unit for aspirin desensitisation during this period. The majority (79%) were clinical admissions for desensitisation; eight (33%) of them developed a hypersensitivity reaction during desensitisation. Half of the latter had only limited cutaneous reactions and were able to complete the desensitisation protocol and developed aspirin tolerance. Overall, 20 (83%) of the patients were successfully desensitised at the initial attempt. No serious adverse reactions occurred in the cohort. Twelve of the patients had significant coronary artery disease revealed by coronary angiography and received a percutaneous coronary intervention, nine of whom received drug-eluting stents while three received bare metal stents due to financial constraints. All 11 successfully desensitised patients received aspirin and clopidogrel as double antiplatelet therapy after percutaneous coronary intervention. The remaining patient had a bare metal stent implant due to failed aspirin desensitisation. CONCLUSION. Given the potentially different genetic basis of aspirin hypersensitivity in different ethnicities, recourse to desensitisation in the Chinese population has not previously been addressed. This study demonstrated that aspirin desensitisation using a rapid protocol can be performed effectively and safely in Chinese patients. Our results were comparable to those in other reported studies involving other ethnicities. Successful aspirin desensitisation permits patients to pursue long-term double antiplatelet therapy that includes aspirin after percutaneous coronary intervention, and thus allows the use of drug-eluting stents as a feasible option. HubMed – drug