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San Francisco, CA, United States

Bova M.P.,Elan Pharmaceutical | Kinney G.G.,Elan Pharmaceutical
Expert Opinion on Orphan Drugs | Year: 2013

Introduction: Amyotrophic lateral sclerosis (ALS) is a progressive and devastating neurodegenerative disease resulting from injury and death of upper and lower motor neurons. Symptoms initially include muscle weakness and twitching and subsequently progress to muscle atrophy, complete loss of limb use, respiratory difficulties and ultimately death. Multiple biological mechanisms have been implicated in ALS and a complex etiology has been described. As a result, drug discovery researchers have few validated targets to pursue and patients have few therapeutic options. Areas covered: Identification of new drug targets in ALS can be facilitated by a detailed understanding of the processes and genes that contribute to pathogenesis. Accordingly, this review summarizes current hypotheses regarding underlying mechanisms for motor neuron susceptibility in ALS. An overview of emerging and tractable drug targets that could result in therapeutic breakthroughs is provided. Expert opinion: Despite the immense progress that has been made in understanding ALS over the last decade, riluzole remains the only approved drug to treat ALS. Combining structure-guided drug design applied to validated and pharmaceutically tractable targets with disease-relevant phenotypic screens will allow for the identification of novel drug targets and potentially breakthrough therapeutics for ALS. © Informa UK, Ltd. Source

Mondal K.,Elan Pharmaceutical | Regnstrom K.,Elan Pharmaceutical | Morishige W.,Elan Pharmaceutical | Barbour R.,Elan Pharmaceutical | And 6 more authors.
Biochemical and Biophysical Research Communications | Year: 2013

Alzheimer's disease (AD) is a devastating neurodegenerative disease affecting millions of people. β-Secretase-1 (BACE-1), an enzyme involved in the processing of the amyloid precursor protein (APP) to form Aβ, is a well validated target for AD. Herein, the authors characterize 10 randomly selected hydroxyethylamine (HEA) BACE-1 inhibitors in terms of their association and dissociation rate constants and thermodynamics of binding using surface plasmon resonance (SPR). Rate constants of association (ka) measured at 25 C ranged from a low of 2.42 × 104 M-1 s -1 to the highest value of 8.3 × 105 M-1 s-1. Rate constants of dissociation (kd) ranged from 1.09 × 10-4 s-1 (corresponding to a residence time of close to three hours), to the fastest of 0.028 s-1. Three compounds were selected for further thermodynamic analysis where it was shown that equilibrium binding was enthalpy driven while unfavorable entropy of binding was observed. Structural analysis revealed that upon ligand binding, the BACE-1flap folds down over the bound ligand causing an induced fit. The maximal difference between alpha carbon positions in the open and closed conformations of the flap was over 5 Å. Thus the negative entropy of binding determined using SPR analysis was consistent with an induced fit observed by structural analysis. © 2013 Elsevier Inc. All rights reserved. Source

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