104096-15-3Relevant articles and documents
NON-PEPTIDE OPIOID RECEPTOR MODULATORS
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, (2020/03/15)
Non-peptide MOR opioid receptor modulators are provided. The compounds exhibit predominantly central activity and are used to treat e.g. opioid addiction. The compounds described herein are generally delivered (administered) in a pharmaceutical compositio
Design, Synthesis, and Biological Evaluation of the Third Generation 17-Cyclopropylmethyl-3,14β-dihydroxy-4,5α-epoxy-6β-[(4′-pyridyl)carboxamido]morphinan (NAP) Derivatives as μ/κ Opioid Receptor Dual Selective Ligands
Zheng, Yi,Obeng, Samuel,Wang, Huiqun,Jali, Abdulmajeed M.,Peddibhotla, Bharath,Williams, Dwight A.,Zou, Chuanchun,Stevens, David L.,Dewey, William L.,Akbarali, Hamid I.,Selley, Dana E.,Zhang, Yan
, p. 561 - 574 (2019/01/30)
μ opioid receptor (MOR) agonists have been widely applied for treating moderate to severe pain. However, numerous adverse effects have been associated with their application, including opioid-induced constipation (OIC), respiratory depression, and addicti
9-Hydroxyazafluorenes and their use in thrombin inhibitors
Stauffer, Kenneth J.,Williams, Peter D.,Selnick, Harold G.,Nantermet, Philippe G.,Newton, Christina L.,Homnick, Carl F.,Zrada, Matthew M.,Lewis, S. Dale,Lucas, Bobby J.,Krueger, Julie A.,Pietrak, Beth L.,Lyle, Elizabeth A.,Singh, Rominder,Miller-Stein, Cynthia,White, Rebecca B.,Wong, Bradley,Wallace, Audrey A.,Sitko, Gary R.,Cook, Jacquelyn J.,Holahan, Marie A.,Stranieri-Michener, Maria,Leonard, Yvonne M.,Lynch Jr., Joseph J.,McMasters, Daniel R.,Yan, Youwei
, p. 2282 - 2293 (2007/10/03)
Optimization of a previously reported thrombin inhibitor, 9-hydroxy-9-fluorenylcarbonyl-L-prolyl-trans-4-aminocyclohexylmethylamide (1), by replacing the aminocyclohexyl P1 group provided a new lead structure, 9-hydroxy-9-fluorenylcarbonyl-L-prolyl-2-aminomethyl-5-chlorobenzylamide (2), with improved potency (Ki = 0.49 nM for human thrombin, 2× APTT = 0.37 μM in human plasma) and pharmacokinetic properties (F = 39%, iv T1/2 = 13 h in dogs). An effective strategy for reducing plasma protein binding of 2 and improving efficacy in an in vivo thrombosis model in rats was to replace the lipophilic fluorenyl group in P3 with an azafluorenyl group. Systematic investigation of all possible azafluorenyl P3 isomers and azafluorenyl-N-oxide analogues of 2 led to the identification of an optimal compound, 3-aza-9-hydroxyfluoren-9(R)-ylcarbonyl-L-prolyl-2-aminomethyl-5- chlorobenzylamide (19b), with high potency (Ki = 0.40 nM, 2× APTT = 0.18 μM), excellent pharmacokinetic properties (F = 55%, T 1/2 = 14 h in dogs), and complete efficacy in the in vivo thrombosis model in rats (inhibition of FeCl3-induced vessel occlusions in six of six rats receiving an intravenous infusion of 10 μg/kg/min of 19b). The stereochemistry of the azafluorenyl group in 19b was determined by X-ray crystallographic analysis of its N-oxide derivative (23b) bound in the active site of human thrombin.
