Showing papers by "Scott P. Runyon published in 2016"
TL;DR: Preliminary SAR, synthetic methodology, and in vitro pharmacological characterization indicate this scaffold will serve as a favorable starting point for further refinement of APJ potency and selectivity.
26 citations
TL;DR: Evaluation of the conformationally constrained series showed that structural rigid compounds having the 3-hydroxyphenyl group locked in the piperidine equatorial orientation had potencies equal to or better than similar compounds having more flexible structures similar to 1.1.0.
Abstract: In order to gain additional information concerning the active conformation of the N-substituted trans-3,4-dimethyl-4-(3-hydroxyphenyl)piperidine (1) class of opioid receptor antagonists, procedures were developed for the synthesis of structurally rigid N-substituted-6-(3-hydroxyphenyl)3-azabicyclo[3.1.0]hexane and 3-methyl-4-(3-hydroxyphenyl)-4-azabicyclo[4.1.0]heptanes. Evaluation of the conformationally constrained series in a [35S]GTPγS assay showed that structural rigid compounds having the 3-hydroxyphenyl group locked in the piperidine equatorial orientation had potencies equal to or better than similar compounds having more flexible structures similar to 1. The studies of the rigid compounds also suggested that the 3-methyl group present in compound 1 type antagonists may not be necessary for their pure opioid antagonist properties.
7 citations
TL;DR: The identification of the first high-affinity NTS2-selective antagonist that is active in vivo and a significant bias between rat and human for compound 9 in the NTS2 binding assay suggest that calcium mobilization is not the signaling pathway involved in NTS2 -mediated analgesia as assessed by the thermal tail-flick model.
Abstract: Neurotensin receptor type 2 (NTS2) compounds display analgesic activity in animal pain models. We have identified the first high-affinity NTS2-selective antagonist (8) that is active in vivo. This study also revealed that the NTS2 FLIPR assay designation for a compound, agonist, partial agonist, and so forth, did not correlate with its in vivo activity as observed in the thermal tail-flick acute model of pain. This suggests that calcium mobilization is not the signaling pathway involved in NTS2-mediated analgesia as assessed by the thermal tail-flick model. Finally, we found a significant bias between rat and human for compound 9 in the NTS2 binding assay.
7 citations
TL;DR: Of the JDTic analogs, (3R)-7-hydroxy-N-(1S)-2-methyl-[4-methyl-4-pyridine-3-yl-carboxamide (3b)) had the best overall binding potency and selectivity in a [(35)S]GTPγS functional assay, and Calculated physiochemical properties for 3b suggest that it will cross the blood-brain barrier.
7 citations
Patent•
09 Dec 2016
TL;DR: In this paper, the authors describe the use of APJ agonistes du recepteur de l'apeline (APJ) and their application in the treatment of cancer.
Abstract: L'invention concerne des agonistes du recepteur de l'apeline (APJ) et des utilisations de ces agonistes.