The Experts below are selected from a list of 93 Experts worldwide ranked by ideXlab platform
Chris Dockendorff - One of the best experts on this subject based on the ideXlab platform.
-
Design and Evaluation of Heterobivalent PAR1–PAR2 Ligands as Antagonists of Calcium Mobilization
ACS medicinal chemistry letters, 2018Co-Authors: Mark W. Majewski, Disha M. Gandhi, Ricardo Rosas, Revathi Kodali, Leggy A. Arnold, Chris DockendorffAbstract:A novel class of bivalent ligands targeting putative protease-activated receptor (PAR) heteromers has been prepared based upon reported antagonists for the subtypes PAR1 and PAR2. Modified versions of the PAR1 antagonist RWJ-58259 containing alkyne adapters were connected via cycloaddition reactions to azide-capped polyethylene glycol (PEG) spacers attached to Imidazopyridazine-based PAR2 antagonists. Initial studies of the PAR1-PAR2 antagonists indicated that they inhibited G alpha q-mediated calcium mobilization in endothelial and cancer cells driven by both PAR1 and PAR2 agonists. Compounds of this novel class hold promise for the prevention of restenosis, cancer cell metastasis, and other proliferative disorders.
-
Design and Evaluation of Heterobivalent PAR1–PAR2 Ligands as Antagonists of Calcium Mobilization
2018Co-Authors: Mark W. Majewski, Disha M. Gandhi, Ricardo Rosas, Revathi Kodali, Leggy A. Arnold, Chris DockendorffAbstract:A novel class of bivalent ligands targeting putative protease-activated receptor (PAR) heteromers has been prepared based upon reported antagonists for the subtypes PAR1 and PAR2. Modified versions of the PAR1 antagonist RWJ-58259 containing alkyne adapters were connected via cycloaddition reactions to azide-capped polyethylene glycol (PEG) spacers attached to Imidazopyridazine-based PAR2 antagonists. Initial studies of the PAR1–PAR2 antagonists indicated that they inhibited G alpha q-mediated calcium mobilization in endothelial and cancer cells driven by both PAR1 and PAR2 agonists. Compounds of this novel class hold promise for the prevention of restenosis, cancer cell metastasis, and other proliferative disorders
Claire Le Manach - One of the best experts on this subject based on the ideXlab platform.
-
medicinal chemistry optimization of antiplasmodial Imidazopyridazine hits from high throughput screening of a softfocus kinase library part 2
Journal of Medicinal Chemistry, 2014Co-Authors: Claire Le Manach, Diego Gonzalez Cabrera, Yassir Younis, Dale Taylor, Lubbe Wiesner, Tanya Paquet, Nina Lawrence, Sylva L Schwager, David Waterson, Michael J WittyAbstract:On the basis of our recent results on a novel series of Imidazopyridazine-based antimalarials, we focused on identifying compounds with improved aqueous solubility and hERG profile while maintaining metabolic stability and in vitro potency. Toward this objective, 41 compounds were synthesized and evaluated for antiplasmodial activity against NF54 (sensitive) and K1 (multidrug resistant) strains of the malaria parasite Plasmodium falciparum and evaluated for both aqueous solubility and metabolic stability. Selected compounds were tested for in vitro hERG activity and in vivo efficacy in the P. berghei mouse model. Several compounds were identified with significantly improved aqueous solubility, good metabolic stability, and a clean hERG profile relative to a previous frontrunner lead compound. A sulfoxide-based Imidazopyridazine analog 45, arising from a prodrug-like strategy, was completely curative in the Plasmodium berghei mouse model at 4 × 50 mg/kg po.
-
medicinal chemistry optimization of antiplasmodial Imidazopyridazine hits from high throughput screening of a softfocus kinase library part 1
Journal of Medicinal Chemistry, 2014Co-Authors: Claire Le Manach, Diego Gonzalez Cabrera, Frederic Douelle, Aloysius T Nchinda, Yassir Younis, Karen L White, Eileen Ryan, Dale Taylor, Lubbe Wiesner, Corinne MarchAbstract:A novel class of Imidazopyridazines identified from whole cell screening of a SoftFocus kinase library was synthesized and evaluated for antiplasmodial activity against K1 (multidrug resistant strain) and NF54 (sensitive strain). Structure-activity relationship studies led to the identification of highly potent compounds against both strains. Compound 35 was highly active (IC50: K1 = 6.3 nM, NF54 = 7.3 nM) and comparable in potency to artesunate, and 35 exhibited 98% activity in the in vivo P. berghei mouse model (4-day test by Peters) at 4 × 50 mg/kg po. Compound 35 was also assessed against P. falciparum in the in vivo SCID mouse model where the efficacy was found to be more consistent with the in vitro activity. Furthermore, 35 displayed high (78%) rat oral bioavailability with good oral exposure and plasma half-life. Mice exposure at the same dose was 10-fold lower than in rat, suggesting lower oral absorption and/or higher metabolic clearance in mice.
-
Medicinal Chemistry Optimization of Antiplasmodial Imidazopyridazine Hits from High Throughput Screening of a SoftFocus Kinase Library: Part 2
2014Co-Authors: Claire Le Manach, Yassir Younis, Dale Taylor, Lubbe Wiesner, Tanya Paquet, Nina Lawrence, David Waterson, Diego Gonzàlez Cabrera, Sylva Schwager, Michael J WittyAbstract:On the basis of our recent results on a novel series of Imidazopyridazine-based antimalarials, we focused on identifying compounds with improved aqueous solubility and hERG profile while maintaining metabolic stability and in vitro potency. Toward this objective, 41 compounds were synthesized and evaluated for antiplasmodial activity against NF54 (sensitive) and K1 (multidrug resistant) strains of the malaria parasite Plasmodium falciparum and evaluated for both aqueous solubility and metabolic stability. Selected compounds were tested for in vitro hERG activity and in vivo efficacy in the P. berghei mouse model. Several compounds were identified with significantly improved aqueous solubility, good metabolic stability, and a clean hERG profile relative to a previous frontrunner lead compound. A sulfoxide-based Imidazopyridazine analog 45, arising from a prodrug-like strategy, was completely curative in the Plasmodium berghei mouse model at 4 × 50 mg/kg po
Dale Taylor - One of the best experts on this subject based on the ideXlab platform.
-
antiplasmodial Imidazopyridazines structure activity relationship studies lead to the identification of analogues with improved solubility and herg profiles
MedChemComm, 2018Co-Authors: Peter Mubanga Cheuka, Dale Taylor, Nina Lawrence, Sergio Wittlin, Kelly ChibaleAbstract:3,6-Diarylated Imidazopyridazines have recently been shown to possess good in vitro antiplasmodial and in vivo antimalarial activity. However, frontrunner compounds have been associated with poor solubility and a hERG (human ether-a-go-go-related gene) inhibition liability raising concerns for potential cardiotoxicity risks. Herein, we report the synthesis and structure–activity relationship studies of new Imidazopyridazines aimed at improving aqueous solubility and countering hERG inhibition while maintaining antiplasmodial potency. While we identified new analogues with potent antiplasmodial activity (IC50 = 0.031 μM against the NF54 drug-sensitive strain, and IC50 = 0.0246 μM against the K1 multidrug resistant strain), hERG inhibition remained an issue. Excitingly, on the other hand, new analogues with a substantially improved hERG inhibition profile (IC50 = 7.83–32.3 μM) with sub-micromolar antiplasmodial activity (NF54, IC50 = 0.151–0.922 μM) were identified. Similarly, the introduced molecular features also resulted in analogues with moderate to high solubility (60–200 μM) while also displaying sub-micromolar antiplasmodial potency (NF54, IC50 = 0.136–0.99 μM).
-
medicinal chemistry optimization of antiplasmodial Imidazopyridazine hits from high throughput screening of a softfocus kinase library part 2
Journal of Medicinal Chemistry, 2014Co-Authors: Claire Le Manach, Diego Gonzalez Cabrera, Yassir Younis, Dale Taylor, Lubbe Wiesner, Tanya Paquet, Nina Lawrence, Sylva L Schwager, David Waterson, Michael J WittyAbstract:On the basis of our recent results on a novel series of Imidazopyridazine-based antimalarials, we focused on identifying compounds with improved aqueous solubility and hERG profile while maintaining metabolic stability and in vitro potency. Toward this objective, 41 compounds were synthesized and evaluated for antiplasmodial activity against NF54 (sensitive) and K1 (multidrug resistant) strains of the malaria parasite Plasmodium falciparum and evaluated for both aqueous solubility and metabolic stability. Selected compounds were tested for in vitro hERG activity and in vivo efficacy in the P. berghei mouse model. Several compounds were identified with significantly improved aqueous solubility, good metabolic stability, and a clean hERG profile relative to a previous frontrunner lead compound. A sulfoxide-based Imidazopyridazine analog 45, arising from a prodrug-like strategy, was completely curative in the Plasmodium berghei mouse model at 4 × 50 mg/kg po.
-
medicinal chemistry optimization of antiplasmodial Imidazopyridazine hits from high throughput screening of a softfocus kinase library part 1
Journal of Medicinal Chemistry, 2014Co-Authors: Claire Le Manach, Diego Gonzalez Cabrera, Frederic Douelle, Aloysius T Nchinda, Yassir Younis, Karen L White, Eileen Ryan, Dale Taylor, Lubbe Wiesner, Corinne MarchAbstract:A novel class of Imidazopyridazines identified from whole cell screening of a SoftFocus kinase library was synthesized and evaluated for antiplasmodial activity against K1 (multidrug resistant strain) and NF54 (sensitive strain). Structure-activity relationship studies led to the identification of highly potent compounds against both strains. Compound 35 was highly active (IC50: K1 = 6.3 nM, NF54 = 7.3 nM) and comparable in potency to artesunate, and 35 exhibited 98% activity in the in vivo P. berghei mouse model (4-day test by Peters) at 4 × 50 mg/kg po. Compound 35 was also assessed against P. falciparum in the in vivo SCID mouse model where the efficacy was found to be more consistent with the in vitro activity. Furthermore, 35 displayed high (78%) rat oral bioavailability with good oral exposure and plasma half-life. Mice exposure at the same dose was 10-fold lower than in rat, suggesting lower oral absorption and/or higher metabolic clearance in mice.
-
Medicinal Chemistry Optimization of Antiplasmodial Imidazopyridazine Hits from High Throughput Screening of a SoftFocus Kinase Library: Part 2
2014Co-Authors: Claire Le Manach, Yassir Younis, Dale Taylor, Lubbe Wiesner, Tanya Paquet, Nina Lawrence, David Waterson, Diego Gonzàlez Cabrera, Sylva Schwager, Michael J WittyAbstract:On the basis of our recent results on a novel series of Imidazopyridazine-based antimalarials, we focused on identifying compounds with improved aqueous solubility and hERG profile while maintaining metabolic stability and in vitro potency. Toward this objective, 41 compounds were synthesized and evaluated for antiplasmodial activity against NF54 (sensitive) and K1 (multidrug resistant) strains of the malaria parasite Plasmodium falciparum and evaluated for both aqueous solubility and metabolic stability. Selected compounds were tested for in vitro hERG activity and in vivo efficacy in the P. berghei mouse model. Several compounds were identified with significantly improved aqueous solubility, good metabolic stability, and a clean hERG profile relative to a previous frontrunner lead compound. A sulfoxide-based Imidazopyridazine analog 45, arising from a prodrug-like strategy, was completely curative in the Plasmodium berghei mouse model at 4 × 50 mg/kg po
Mark W. Majewski - One of the best experts on this subject based on the ideXlab platform.
-
Design and Evaluation of Heterobivalent PAR1–PAR2 Ligands as Antagonists of Calcium Mobilization
ACS medicinal chemistry letters, 2018Co-Authors: Mark W. Majewski, Disha M. Gandhi, Ricardo Rosas, Revathi Kodali, Leggy A. Arnold, Chris DockendorffAbstract:A novel class of bivalent ligands targeting putative protease-activated receptor (PAR) heteromers has been prepared based upon reported antagonists for the subtypes PAR1 and PAR2. Modified versions of the PAR1 antagonist RWJ-58259 containing alkyne adapters were connected via cycloaddition reactions to azide-capped polyethylene glycol (PEG) spacers attached to Imidazopyridazine-based PAR2 antagonists. Initial studies of the PAR1-PAR2 antagonists indicated that they inhibited G alpha q-mediated calcium mobilization in endothelial and cancer cells driven by both PAR1 and PAR2 agonists. Compounds of this novel class hold promise for the prevention of restenosis, cancer cell metastasis, and other proliferative disorders.
-
Design and Evaluation of Heterobivalent PAR1–PAR2 Ligands as Antagonists of Calcium Mobilization
2018Co-Authors: Mark W. Majewski, Disha M. Gandhi, Ricardo Rosas, Revathi Kodali, Leggy A. Arnold, Chris DockendorffAbstract:A novel class of bivalent ligands targeting putative protease-activated receptor (PAR) heteromers has been prepared based upon reported antagonists for the subtypes PAR1 and PAR2. Modified versions of the PAR1 antagonist RWJ-58259 containing alkyne adapters were connected via cycloaddition reactions to azide-capped polyethylene glycol (PEG) spacers attached to Imidazopyridazine-based PAR2 antagonists. Initial studies of the PAR1–PAR2 antagonists indicated that they inhibited G alpha q-mediated calcium mobilization in endothelial and cancer cells driven by both PAR1 and PAR2 agonists. Compounds of this novel class hold promise for the prevention of restenosis, cancer cell metastasis, and other proliferative disorders
Michael J Witty - One of the best experts on this subject based on the ideXlab platform.
-
medicinal chemistry optimization of antiplasmodial Imidazopyridazine hits from high throughput screening of a softfocus kinase library part 2
Journal of Medicinal Chemistry, 2014Co-Authors: Claire Le Manach, Diego Gonzalez Cabrera, Yassir Younis, Dale Taylor, Lubbe Wiesner, Tanya Paquet, Nina Lawrence, Sylva L Schwager, David Waterson, Michael J WittyAbstract:On the basis of our recent results on a novel series of Imidazopyridazine-based antimalarials, we focused on identifying compounds with improved aqueous solubility and hERG profile while maintaining metabolic stability and in vitro potency. Toward this objective, 41 compounds were synthesized and evaluated for antiplasmodial activity against NF54 (sensitive) and K1 (multidrug resistant) strains of the malaria parasite Plasmodium falciparum and evaluated for both aqueous solubility and metabolic stability. Selected compounds were tested for in vitro hERG activity and in vivo efficacy in the P. berghei mouse model. Several compounds were identified with significantly improved aqueous solubility, good metabolic stability, and a clean hERG profile relative to a previous frontrunner lead compound. A sulfoxide-based Imidazopyridazine analog 45, arising from a prodrug-like strategy, was completely curative in the Plasmodium berghei mouse model at 4 × 50 mg/kg po.
-
Medicinal Chemistry Optimization of Antiplasmodial Imidazopyridazine Hits from High Throughput Screening of a SoftFocus Kinase Library: Part 2
2014Co-Authors: Claire Le Manach, Yassir Younis, Dale Taylor, Lubbe Wiesner, Tanya Paquet, Nina Lawrence, David Waterson, Diego Gonzàlez Cabrera, Sylva Schwager, Michael J WittyAbstract:On the basis of our recent results on a novel series of Imidazopyridazine-based antimalarials, we focused on identifying compounds with improved aqueous solubility and hERG profile while maintaining metabolic stability and in vitro potency. Toward this objective, 41 compounds were synthesized and evaluated for antiplasmodial activity against NF54 (sensitive) and K1 (multidrug resistant) strains of the malaria parasite Plasmodium falciparum and evaluated for both aqueous solubility and metabolic stability. Selected compounds were tested for in vitro hERG activity and in vivo efficacy in the P. berghei mouse model. Several compounds were identified with significantly improved aqueous solubility, good metabolic stability, and a clean hERG profile relative to a previous frontrunner lead compound. A sulfoxide-based Imidazopyridazine analog 45, arising from a prodrug-like strategy, was completely curative in the Plasmodium berghei mouse model at 4 × 50 mg/kg po
