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Mammen M.,Theravance, Inc. | Stangeland E.L.,Theravance, Inc. | Steinfeld T.,Theravance, Inc. | Aiyar J.,Theravance, Inc.
Naunyn-Schmiedeberg's Archives of Pharmacology | Year: 2011

β-Adrenoceptors are important mediators of smooth muscle relaxation in the urinary bladder, but the concomitant presence of a muscarinic agonist, e.g., carbachol, can attenuate relaxation responses by reducing potency and/or efficacy of β-adrenoceptor agonists such as isoprenaline. Therefore, the present study was designed to explore the subtypes and signalling pathways of muscarinic receptors involved in the attenuation of isoprenaline-induced isolated rat detrusor preparations using novel subtype-selective receptor ligands. In radioligand binding studies, we characterized BZI to be a M 3-sparing muscarinic agonist, providing selective M 2 stimulation in rat bladder, and THRX-182087 as a highly M 2-selective antagonist. The use of BZI and of THRX-182087 in the presence of carbachol enabled experimental conditions with a selective stimulation of only M 2 or M 3 receptors, respectively. Confirming previous findings, carbachol attenuated isoprenaline-induced detrusor relaxation. M 2-selective stimulation partly mimicked this attenuation, indicating that both M 2 and M 3 receptors are involved. During M 3-selective stimulation, the attenuation of isoprenaline responses was reduced by the phospholipase C inhibitor U 73,122 but not by the protein kinase C inhibitor chelerythrine. We conclude that both M 2 and M 3 receptors contribute to attenuation of β-adrenoceptor-mediated relaxation of rat urinary bladder; the signal transduction pathway involved in the M 3 component of this attenuation differs from that mediating direct contractile effects of M 3 receptors. © 2011 The Author(s).


Shen F.,Theravance, Inc. | Smith J.A.M.,Theravance, Inc. | Chang R.,Theravance, Inc. | Bourdet D.L.,Theravance, Inc. | And 3 more authors.
Neuropharmacology | Year: 2011

There remains an urgent need for therapeutic agents that provide improved symptomatic treatment and attenuate disease progression in patients with Alzheimer's disease (AD). 5-HT 4 receptors are widely expressed in those CNS areas which receive substantial cholinergic input and are involved in cognition. The ability of 5-HT 4 receptor agonists to increase acetylcholine (ACh) release and reduce cognitive impairment in both animals and humans has been demonstrated. In addition, 5-HT 4 receptor agonist modulation of levels of the amyloid precursor protein (APP) derived peptides, soluble amyloid precursor protein (sAPPα) and amyloid beta protein (Aβ) in the CNS has been reported. In this study, the preclinical properties of three structurally-distinct 5-HT 4 receptor selective agonists, PRX-03140, velusetrag and TD-8954, were studied to assess their potential for symptomatic and disease-modifying benefit in the treatment of AD. All three compounds exhibited high affinity for the rat 5-HT 4 receptor but could be discriminated on the basis of their agonist activity. In cAMP accumulation and sAPPα secretion assays using recombinant HEK293f-5-HT 4(d)-APP 695 cells, velusetrag and TD-8954 were potent, full agonists, relative to 5-HT, whereas PRX-03140 was a partial agonist (intrinsic activity 18%, relative to 5-HT). In a guinea pig colon isolated tissue preparation, TD-8954 exhibited lower intrinsic activity than velusetrag, and PRX-03140 had negligible agonist activity. In the rat Morris water maze (MWM) cognition test, velusetrag and TD-8954 (0.1 mg/kg), but not PRX-03140 (0.03-1 mg/kg), significantly reversed the scopolamine-induced spatial learning deficit via activation of 5-HT 4 receptors. Coadministration of subefficacious doses of the acetylcholinesterase inhibitor (AChEi), donepezil (0.1 mg/kg, i.p.), and either velusetrag or TD-8954 (0.01 mg/kg i.p.) resulted in reversal of the scopolamine-induced cognitive deficit. Pharmacokinetic data indicated that the CNS penetration for all three 5-HT 4 receptor agonists was relatively low. However, the pharmacodynamic-pharmacokinetic relationships in the MWM model for velusetrag and TD-8954 were consistent with their respective receptor pharmacology (binding affinity and intrinsic efficacy) and CNS penetration properties. Collectively, these findings support a potential role for potent and efficacious 5-HT 4 receptor agonists in the treatment of AD. © 2011 Elsevier Ltd. All rights reserved.


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.


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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