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Start Over Author "Peters MF" Publisher elsevier science ltd
2 results on '"Peters MF"'

1. Discovery of 8-azabicyclo[3.2.1]octan-3-yloxy-benzamides as selective antagonists of the kappa opioid receptor. Part 1.

Author

Brugel TA, Smith RW, Balestra M, Becker C, Daniels T, Hoerter TN, Koether GM, Throner SR, Panko LM, Folmer JJ, Cacciola J, Hunter AM, Liu R, Edwards PD, Brown DG, Gordon J, Ledonne NC, Pietras M, Schroeder P, Sygowski LA, Hirata LT, Zacco A, and Peters MF

Subjects
Animals, Benzamides chemical synthesis, Benzamides pharmacokinetics, Cell Line, Tumor, Diuresis drug effects, Drug Evaluation, Preclinical, High-Throughput Screening Assays, Humans, Microsomes, Liver metabolism, Rats, Receptors, Opioid, kappa metabolism, Structure-Activity Relationship, Tropanes chemical synthesis, Tropanes pharmacokinetics, Benzamides chemistry, Receptors, Opioid, kappa antagonists & inhibitors, Tropanes chemistry
Abstract

Initial high throughput screening efforts identified highly potent and selective kappa opioid receptor antagonist 3 (κ IC(50)=77 nM; μ:κ and δ:κ IC(50) ratios>400) which lacked CNS exposure in vivo. Modification of this scaffold resulted in development of a series of 8-azabicyclo[3.2.1]octan-3-yloxy-benzamides showing potent and selectivity κ antagonism as well as good brain exposure. Analog 6c (κ IC(50)=20 nM; μ:κ=36, δ:κ=415) was also shown to reverse κ-agonist induced rat diuresis in vivo., (Copyright © 2010. Published by Elsevier Ltd.)

Published
2010
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2. SAR development of a series of 8-azabicyclo[3.2.1]octan-3-yloxy-benzamides as kappa opioid receptor antagonists. Part 2.

Author

Brugel TA, Smith RW, Balestra M, Becker C, Daniels T, Koether GM, Throner SR, Panko LM, Brown DG, Liu R, Gordon J, and Peters MF

Subjects
Animals, Antidepressive Agents chemical synthesis, Antidepressive Agents pharmacokinetics, Benzamides chemical synthesis, Benzamides pharmacokinetics, Brain metabolism, Bridged Bicyclo Compounds chemical synthesis, Bridged Bicyclo Compounds chemistry, Bridged Bicyclo Compounds pharmacokinetics, Bridged Bicyclo Compounds pharmacology, Depressive Disorder, Major drug therapy, Humans, Microsomes, Liver metabolism, Rats, Structure-Activity Relationship, Antidepressive Agents chemistry, Antidepressive Agents pharmacology, Benzamides chemistry, Benzamides pharmacology, Receptors, Opioid, kappa antagonists & inhibitors, Receptors, Opioid, kappa metabolism
Abstract

Further structure activity relationship studies on a previously reported 8-azabicyclo[3.2.1]octan-3-yloxy-benzamide series of potent and selective kappa opioid receptor antagonists is discussed. Modification of the pendant N-substitution to include a cyclohexylurea moiety produced analogs with greater in vitro opioid and hERG selectivity such as 12 (kappa IC50=172 nM, mu:kappa ratio=93, delta:kappa ratio=>174, hERG IC50=>33 microM). Changes to the linker conformation and identity as well as to the benzamide ring moiety were also investigated., (Copyright (c) 2010. Published by Elsevier Ltd.)

Published
2010
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