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Song Y.,Illinois State University | Lunde C.S.,Theravance, Inc. | Benton B.M.,Theravance, Inc. | Benton B.M.,Novartis | Wilkinson B.J.,Illinois State University
Microbial Drug Resistance | Year: 2013

Telavancin is a novel semisynthetic lipoglycopeptide derivative of vancomycin with a dual mode of action. This study sought to understand the mechanisms of decreased telavancin susceptibility in a laboratory-derived Staphlococcus aureus mutant TlvDSMED1952. There were extensive changes in the transcriptome of TlvDSMED1952 compared to the susceptible parent strain MED1951. Genes upregulated included cofactor biosynthesis genes, cell wall-related genes, fatty acid biosynthesis genes, and stress genes. Downregulated genes included lysine operon biosynthesis genes and lrgB, which are induced by telavancin in susceptible strains, agr and kdpDE genes, various cell surface protein genes, phenol-soluble modulin genes, several protease genes, and genes involved in anaerobic metabolism. The decreased susceptibility mutant had somewhat thicker cell walls and a decreased autolytic activity that may be related to decreased proteolytic peptidoglycan hydrolase processing. Membrane fatty acid changes correlated with increased membrane fluidity were observed. It seems likely that there are multiple genetic changes associated with the development of decreased telavancin susceptibility. The TlvDS mutant showed some similar features to vancomycin-intermediate S. aureus and decreased daptomycin susceptibility strains, but also exhibited its own unique features. © 2013, Mary Ann Liebert, Inc. 2013.


Ferslew B.C.,University of North Carolina at Chapel Hill | Ferslew B.C.,Theravance, Inc. | Kock K.,University of North Carolina at Chapel Hill | Kock K.,Amgen Inc. | And 2 more authors.
Drug Metabolism and Disposition | Year: 2014

Hepatic uptake and efflux transporters govern the systemic and hepatic exposure of many drugs and metabolites. Enalapril is a pharmacologically inactive prodrug of enalaprilat. Following oral administration, enalapril is converted to enalaprilat in hepatocytes and undergoes translocation into the systemic circulation to exert its pharmacologic effect by inhibiting angiotensin-converting enzyme. Although the transport proteins governing hepatic uptake of enalapril and the biliary excretion of enalapril and enalaprilat are well established, it remains unknown how hepatically derived enalaprilat translocates across the basolateral membrane into the systemic circulation. In this study, the role of ATP-binding cassette transporters in the hepatic basolateral efflux of enalaprilat was investigated using membrane vesicles. ATP-dependent uptake of enalaprilat into vesicles expressing multidrug resistance-associated protein (MRP) 4 was significantly greater (∼3.8-fold) than in control vesicles. In contrast, enalaprilat was not transported to a significant extent by MRP3, and enalapril was not transported by either MRP3 or MRP4. The functional importance of MRP4 in the basolateral excretion of derived enalaprilat was evaluated using a novel basolateral efflux protocol developed in human sandwich-cultured hepatocytes. Under normal culture conditions, the mean intrinsic basolateral efflux clearance (CLint,basolateral) of enalaprilat was 0.026 ± 0.012 μl/min; enalaprilat CL int,basolateral was significantly reduced to 0.009 ± 0.009 μl/min by pretreatment with the pan-MRP inhibitor MK-571. Results suggest that hepatically derived enalaprilat is excreted across the hepatic basolateral membrane by MRP4. Changes in MRP4-mediated basolateral efflux may alter the systemic concentrations of this active metabolite, and potentially the efficacy of enalapril. Copyright © 2014 by The American Society for Pharmacology and Experimental Therapeutics.


Hughes A.D.,Theravance, Inc. | McNamara A.,Theravance, Inc. | Steinfeld T.,Theravance, Inc.
Progress in Medicinal Chemistry | Year: 2012

Inhaled beta-2-adrenergic receptor (β 2) agonists and inhaled muscarinic acetylcholine antagonists are the most frequently used bronchodilators in the treatment of chronic obstructive pulmonary disease. While short-acting agents (4-6 h) serve as 'rescue' therapy, long-acting (12-24 h) bronchodilators can reduce the incidence and number of exacerbations as well as improve lung function. Due to the complementary nature of the two mechanisms, combinations of the two classes provide even greater improvement in lung function than either mechanism alone. This review focuses on the multivalent origins of dual pharmacology MABA bronchodilators and describes the supporting in vitro characterization and reported animal studies. Topics discussed include approaches taken to identify novel MABA molecules, highlighting preferred muscarinic and β 2-binding groups and how these two entities are linked together; challenges in designing MABA molecules; and the potential benefits of enhanced bronchoprotection and opportunity for 'triple therapy' with an inhaled corticosteroid. © 2012 Elsevier B.V. All rights reserved.


Krause K.M.,Theravance, Inc. | Barriere S.L.,Theravance, Inc. | Kitt M.M.,Theravance, Inc. | Benton B.M.,Theravance, Inc.
Diagnostic Microbiology and Infectious Disease | Year: 2010

During phase 3 clinical studies of telavancin for treatment of complicated skin and skin structure infections, a total of 1530 aerobic Gram-positive isolates were identified at baseline. The majority of these strains were Staphylococcus aureus (n = 1214; 62% methicillin-resistant). All isolates were inhibited by ≤1 μg/mL of telavancin. © 2010 Elsevier Inc.


Samame R.A.,University of California at Irvine | Owens C.M.,Theravance, Inc. | Rychnovsky S.D.,University of California at Irvine
Chemical Science | Year: 2015

(+)-Fastigiatine was assembled in six steps from (R)-5-methylcyclohex-2-en-1-one. Intermolecular Diels-Alder reaction introduced most of the carbon atoms for the target. The two Boc-protected nitrogen atom building blocks were introduced by a Suzuki coupling and a cuprate addition. A biomimetic transannular Mannich reaction generated the two quaternary centers at a late stage. Each step builds core bonds, and combined with a minimalist protecting group strategy, this approach led to a very concise synthesis.


Shen F.,Theravance, Inc. | Tsuruda P.R.,Theravance, Inc. | Smith J.A.M.,Theravance, Inc. | Obedencio G.P.,Theravance, Inc. | Martin W.J.,Theravance, Inc.
PLoS ONE | Year: 2013

Multimodal analgesia is designed to optimize pain relief by coadministering drugs with distinct mechanisms of action or by combining multiple pharmacologies within a single molecule. In clinical settings, combinations of monoamine reuptake inhibitors and opioid receptor agonists have been explored and one currently available analgesic, tapentadol, functions as both a μ-opioid receptor agonist and a norepinephrine transporter inhibitor. However, it is unclear whether the combination of selective norepinephrine reuptake inhibition and μ-receptor agonism achieves an optimal antinociceptive synergy. In this study, we assessed the pharmacodynamic interactions between morphine and monoamine reuptake inhibitors that possess different affinities and selectivities for norepinephrine and serotonin transporters. Using the rat formalin model, in conjunction with measurements of ex vivo transporter occupancy, we show that neither the norepinephrine-selective inhibitor, esreboxetine, nor the serotonin-selective reuptake inhibitor, fluoxetine, produce antinociceptive synergy with morphine. Atomoxetine, a monoamine reuptake inhibitor that achieves higher levels of norepinephrine than serotonin transporter occupancy, exhibited robust antinociceptive synergy with morphine. Similarly, a fixed-dose combination of esreboxetine and fluoxetine which achieves comparable levels of transporter occupancy potentiated the antinociceptive response to morphine. By contrast, duloxetine, a monoamine reuptake inhibitor that achieves higher serotonin than norepinephrine transporter occupancy, failed to potentiate the antinociceptive response to morphine. However, when duloxetine was coadministered with the 5-HT3 receptor antagonist, ondansetron, potentiation of the antinociceptive response to morphine was revealed. These results support the notion that inhibition of both serotonin and norepinephrine transporters is required for monoamine reuptake inhibitor and opioid-mediated antinociceptive synergy; yet, excess serotonin, acting via 5-HT3 receptors, may reduce the potential for synergistic interactions. Thus, in the rat formalin model, the balance between norepinephrine and serotonin transporter inhibition influences the degree of antinociceptive synergy observed between monoamine reuptake inhibitors and morphine. © 2013 Shen et al.


Secretory diarrhea remains a global health challenge in the developing and developed countries. Secretory or infectious diarrhea is caused by infection of the gastrointestinal tract with a bacterial, viral, or parasitic pathogen. Acute diarrheal diseases have a major impact on morbidity and mortality across the world, with as many as four billion cases occurring annually. Diarrheal disease is responsible for the approximately 1.7 million deaths in children under 5 years old annually. Preventative healthcare measures include safe and effective vaccines and improved water, sanitation, hygiene systems, and nutritional practices. Treatment options in developing countries are usually supportive, replacing intestinal fluid losses with oral rehydration solution (ORS). Oral rehydration therapy (ORT) is well accepted as the most effective treatment for rehydration of children with acute diarrhea and is recommended by the World Health Organization for the prevention and management of dehydration. Its use has resulted in a significant reduction in diarrhea-related mortality. ORT has been recently complemented by zinc supplementation therapy. Rehydration has little effect on stool volume or frequency; therefore, the World Health Organization has recommended that anti-secretory drug treatment be added to rehydration therapy as long as the treatment has proven safe and efficacious in the pediatric population. In the developing countries, Hydrasec™ (racecadotril) is the most widely used antisecretory antidiarrheal, particularly in children. This review focuses on recent advances in the discovery and development of medicines and pharmacological mechanisms that modulate the secretory component of diarrhea that could be efficacious in the treatment of infectious diarrhea in the developing countries, particularly in the pediatric population. © 2011 Springer-Verlag Berlin Heidelberg.


The invention provides biphenyl derivatives of formula 1: wherein R^(1), R^(2), R^(3), R^(4), R^(5), R^(6), R^(7), W, a, b and c are as defined in the specification, or a pharmaceutically acceptable salt or solvate or stereoisomer thereof. The biphenyl derivatives of this invention possess both _(2) adrenergic receptor agonist and muscarinic receptor antagonist activity and therefore, such biphenyl derivatives are useful for treating pulmonary disorders, such as chronic obstructive pulmonary disease and asthma.


Patent
Theravance, Inc. | Date: 2012-09-05

Disclosed are hydrochloride salts of telavancin having a chloride ion content of from 3.7 wt. % to 4.4 wt. %. The disclosed salts have improved stability during storage at ambient temperatures compared to other hydrochloride salts.


A compound of formula I:

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