Current Opinion in Investigational Drugs

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The next issue of this journal (Vol 7 No 2 February 2006) Will contain: Anti-infectives Robin Cooper, Simon Croft, Christian Hubschwerlen, Jeffrey H Toney, Alan Johnson, Barney Koszalka, Nicholas Meanwell, Rino Rappuoli, John Rex & David A Stevens Barney Koszalka & Nicholas Meanwell Editorial overview: Viral entry mechanisms Mark Erion HepDirect prodrugs for targeting nucleotide-based antiviral drugs to the liver Asim Kumar Debnath Prospects and strategies for the discovery and development of small-molecule inhibitors of six-helix bundle formation in class 1 viral fusion proteins Robert Smolic, Martina Volarevic, Catherine H Wu & George Y Wu Potential applications of siRNA in hepatitis C virus therapy Larry Boone Next generation non-nucleoside reverse transcriptase inhibitors for the treatment of HIV Maria Zambon Influenza immunization strategies David Koelle Novel treatment options for herpes simplex virus Ursula Theuretzbacher & Jeffrey H Toney Nature's clarion call of antibacterial resistance: Are we listening? David Shlaes Novel tetracyclines David Kaufman Veronate (Inhibitex) Joseph Jao-Yiu Sung & Henry Lik-Yuen Chan HBV-ISS (Dynavax) David McMillan StreptAvax (ID Biomedical)
Paper alert A selection of interesting recently published papers from major journals relating to drug discovery and research. Current Opinion in Investigational Drugs 2006 7(1):1-3 © The Thomson Corporation ISSN 1472-4472 Contents 1 Anti-infectives 2 Endocrine & metabolic 2 Oncological Anti-infectives Selected by Mohsen Daneshtalab (Memorial University, St John's, NL, Canada) In vitro and in vivo antibacterial activities of SM-216601, a new broad-spectrum parenteral carbapenem. Ueda Y, Kanazawa K, Eguchi K, Takemoto K, Eriguchi Y, Sunagawa M (Sumitomo Pharmaceuticals Research Division, Osaka, Japan). Antimicrob Agents Chemother (2005) 49(10):4185-4196. •• Significance The emergence of multidrug-resistant, Grampositive bacteria such as methicillin-resistant Staphylococcus aureus (MRSA), penicillin-resistant Streptococcus pneumoniae (PRSP) and vancomycin-resistant enterococci (VRE), has affected the usefulness of antibacterial chemotherapy in recent years. Resistance to β-lactam antibiotics is a serious concern because this class of compounds exhibits several advantages over other antibacterials. Thus, there is an urgent need for new β-lactam agents effective against resistant pathogens. These researchers previously reported that 2-(4-arylthiazole-2-ylthio)- 1β-methylcarbapenems, such as SM-17466 (Sumitomo Seika Chemicals Co Ltd/F Hoffmann-La Roche Ltd) and its derivatives, showed potent activity against MRSA owing to their high affinity for penicillin-binding protein (PBP)2a. SM-17466 was also effective against Enterococcus faecium compared with other carbapenems. These observations prompted the search for novel carbapenems with potent activity against MRSA and VRE. SM-216601 (Sumitomo Seika Chemicals Co Ltd/F Hoffmann-La Roche Ltd), a dihydropyrrolyl thiazole analog of SM-17466, was identified, which demonstrated broad-spectrum antibacterial activity against Gram-positive and Gram-negative bacteria. This paper describes in vitro studies investigating the activity of SM-216601 against different clinical isolates compared with vancomycin, linezolid and several other β-lactams. In addition, the efficacy of SM-216601 against systemic infections in mice caused by methicillin-sensitive S aureus, MRSA, Escherichia coli, Pseudomonas aeruginosa and experimental E faecium subcutaneous abscesses is described. Findings This study investigated the in vitro antibacterial activity, affinity for bacterial PBPs and resistance to hydrolysis by dehydropeptidase (DHP)-1 of SM-216601, and evaluated its in vivo efficacy against Gram-positive and Gram-negative bacteria and pharmacokinetics in mice. SM-216601 exhibited potent activity against MRSA, PRSP, VRE, ampicillin-resistant Haemophilus influenzae, Moraxella catarrhalis, E coli, Klebsiella pneumoniae and Proteus mirabilis. In addition, SM-216601 was highly efficacious against experimentally induced infections in mice caused by S aureus, E faecium, E coli and P aeruginosa. Its sensitivity against renal DHP-1 was similar to that of meropenem and superior to that of imipenem. SM-216601 exhibited improved pharmacokinetics compared with imipenem and meropenem in mice, rats, dogs and cynomolgus monkeys. Design, synthesis, and biological activity of m-tyrosinebased 16- and 17-membered macrocyclic inhibitors of hepatitis C virus NS3 serine protease. Chen KX, Njoroge FG, Pichardo J, Prongay A, Butkiewicz N, Yao N, Madison V, Girijavallabhan V (Schering-Plough Research Institute, Kenilworth, NJ, USA). J Med Chem (2005) 48(20):6229-6235. • Significance The worldwide spread of hepatitis C virus (HCV) infection has caused a global health crisis. The only therapies currently available for the treatment of HCV infection are subcutaneous interferon (IFN)α or pegylated IFNα monotherapy, or the combination of IFNα or pegylated IFNα and oral ribavirin. These therapies have limited efficacies and cause considerable side effects in patients. Therefore, the search for small molecules with high efficacy and less toxicity continues. The viral NS3 protein and its corresponding enzyme, NS3 protease, are attractive drug targets in HCV. Many protease inhibitors that have peptidic molecular structures have been developed in recent years. However, because of low bioavailability and poor pharmacokinetics, most of these inhibitors have failed to make it onto the market. Peptidomimetics are peptidic analogs that resist hydrolytic enzymes while exhibiting the same enzyme inhibitory characteristics as the corresponding peptides. The potential of cyclic hexapeptides as inhibitors of the HCV NS3 protease have been reported in a number of studies. Based on these discoveries, novel 16- and 17-membered ring analogs were synthesized and evaluated for HCV NS3 protease inhibitory activity. Findings The synthesis of these cyclic peptides began with the coupling of the commercially available N-Boccyclohexylglycine and m-tyrosine methyl ester, which in five steps gave rise to methyl 11(S)-cyclohexyl-9.12-dioxo-2-oxa- 10,13-diazabicyclo[14.3.1]eicosa-1(20),16,18-triene-14(S)carboxylate. Hydrolysis of this intermediate followed by coupling with [2-(3-amino-2-hydroxy-hexanoylamino)acetylamino]-phenylacetic acid tert-butyl ester hydrochloride afforded the desired 17-membered macrocyclic compounds as either O-tert-butyl ester, free carboxylic acid, or the corresponding mono- or dimethylamide analogs. The corresponding 16-membered analogs were synthesized in the same manner as above. In an HCV protease continuous assay, the 16-membered analogs were less active than the corresponding 17-membered analogs. This study confirmed the potential of these 17-membered macrocycles as lead compounds for further development of anti-HCV drugs. Synthesis and structure-activity relationships of novel anti-hepatitis C agents: N 3 ,5'-cyclo-4-(β-D-ribofuranosyl)vic-triazolo[4,5-b]pyridin-5-one derivatives. Wang P, Du J, Rachakonda S, Chun B-K, Tharnish PM, Stuyver LJ, Otto MJ, Schinazi RF, Watanabe KA (Pharmasset Inc, Princeton, NJ, USA). J Med Chem (2005) 48(20):6454-6460. • Significance Chronic hepatitis C virus (HCV) infection is 1
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