- Optimization of an Imidazo[1,2-a]pyridine Series to Afford Highly Selective Type I1/2 Dual Mer/Axl Kinase Inhibitors within VivoEfficacy
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Inhibition of Mer and Axl kinases has been implicated as a potential way to improve the efficacy of current immuno-oncology therapeutics by restoring the innate immune response in the tumor microenvironment. Highly selective dual Mer/Axl kinase inhibitors are required to validate this hypothesis. Starting from hits from a DNA-encoded library screen, we optimized an imidazo[1,2-a]pyridine series using structure-based compound design to improve potency and reduce lipophilicity, resulting in a highly selectivein vivoprobe compound32. We demonstrated dose-dependentin vivoefficacy and target engagement in Mer- and Axl-dependent efficacy models using two structurally differentiated and selective dual Mer/Axl inhibitors. Additionally,in vivoefficacy was observed in a preclinical MC38 immuno-oncology model in combination with anti-PD1 antibodies and ionizing radiation.
- Boyd, Scott,Brown, Martin R.,Coen, Muireann,Collingwood, Olga,Davies, Nichola L.,Doherty, Ann,Fairley, Gary,Goldberg, Kristin,Hardaker, Elizabeth,He, Guang,Hennessy, Edward J.,Hodgson, George,Hopcroft, Philip,Jackson, Anne,Jiang, Xiefeng,Karmokar, Ankur,Lainé, Anne-Laure,Lindsay, Nicola,Mao, Yumeng,Markandu, Roshini,McCoull, William,McLean, Neville,McMurray, Lindsay,Mooney, Lorraine,Musgrove, Helen,Nissink, J. Willem M.,Pflug, Alexander,Rawlins, Philip B.,Reddy, Venkatesh Pilla,Rivers, Emma,Schimpl, Marianne,Smith, Graham F.,Smith, Paul D.,Tentarelli, Sharon,Travers, Jon,Troup, Robert I.,Walton, Josephine,Wang, Cheng,Wilkinson, Stephen,Williamson, Beth,Winter-Holt, Jon,Yang, Dejian,Zheng, Yuting,Zhu, Qianxiu
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supporting information
p. 13524 - 13539
(2021/09/20)
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- A convenient synthesis of 5-substituted 2-amino-1,3,4-oxadiazoles from corresponding acylthiosemicarbazides using iodine and Oxone
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A convenient methodology has been developed for the synthesis of substituted 2-amino-1,3,4-oxadiazoles from corresponding acylthiosemicarbazides using catalytic amount of iodine/KI in the presence of Oxone as a bulk oxidant. This offers the adv
- Shinde, Vikas N.,Ugarkar, Bheemarao G.,Ghorpade, Sandeep R.
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- Synthesis of 1,3,4-oxadiazoles from 1,2-diacylhydrazines using [Et 2NSF2]BF4 as a practical cyclodehydration agent
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The preparation of 1,3,4-oxadiazoles from 1,2-diacylhydrazines using XtalFluor-E ([Et2NSF2]BF4) as cyclodehydration reagent is described. Various functionalized 1,3,4-oxadiazoles were synthesized and it was found that the use of acetic acid as an additive generally improved the yields.
- Pouliot, Marie-France,Angers, Laetitia,Hamel, Jean-Denys,Paquin, Jean-Francois
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p. 988 - 993
(2012/04/10)
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- Efficient one-pot synthesis of substituted 2-amino-1,3,4-oxadiazoles
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A convenient one-pot method for the preparation of substituted 2-amino-1,3,4-oxadiazoles has been developed. The method is a significant improvement over previously reported syntheses. Reaction of carboxylic acids with thiosemicarbazides afforded the corresponding oxadiazoles in moderate to good yields. In general, the products precipitated from the reaction mixture, and were collected by filtration. In most of the cases, no chromatographic separations were required. To explore the scope and limitations of this reaction, various aliphatic, aromatic, and heteroaromatic carboxylic acids were reacted with different substituted thiosemicarbazides. The influence of R1 and R2 substituents on the reaction yield and additional results demonstrating the versatility of this method are presented.
- Piatnitski Chekler, Eugene L.,Elokdah, Hassan M.,Butera, John
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supporting information; body text
p. 6709 - 6711
(2009/04/07)
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- Efficient one-pot preparation of 5-substituted-2-amino-1,3,4-oxadiazoles using resin-bound reagents
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A robust one-pot solution-phase synthesis of 2-amino-1,3,4-oxadiazoles directly from acylhydrazines and isothiocyanates is described. Commercially-available polymer-supported reagents help facilitate both cyclization and purification. This convenient meth
- Coppo, Frank T.,Evans, Karen A.,Graybill, Todd L.,Burton, George
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p. 3257 - 3260
(2007/10/03)
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- Photoinduced molecular rearrangements. Some comments on the ring-photoisomerization of 1,2,4-oxadiazoles into 1,3,4-oxadiazoles
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The ring-photoisomerization of 3-amino- and 3-methylamino-5-phenyl-1,2,4-oxadiazoles into the corresponding 2-amino- and 2-methylamino-5-phenyl-1,3,4-oxadiazoles has been reinvestigated by examining the effect of a base on the photoreaction. On irradiatin
- Buscemi,Pace,Vivona,Caronna
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p. 777 - 780
(2007/10/03)
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- Photochemical Behaviour of Some 1,2,4-Oxadiazole Derivatives
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The photochemical behaviour of some 1,2,4-oxadiazole derivatives in methanol has been studied at 254 nm.On irradiation, 3-amino- (or 3-methylamino-) 5-aryl-1,2,4-oxadiazoles underwent a ring photoisomerization to 1,3,4-oxadiazoles, probably through a 'rin
- Buscemi, Silvestre,Cicero, Maria G.,Vivona, Nicolo,Caronna, Tullio
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p. 1313 - 1316
(2007/10/02)
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- Oxidation of Aldehyde Semicarbazones with Lead Dioxide: Application to the Syntheses of 2-Amino-1,3,4-oxadiazoles and 2,4-Dihydro-1,2,4-triazol-3-ones
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The oxidation of aldehyde semicarbazones with lead dioxide in acid media was effected.The 4,4-disubstituted semicarbazones of aromatic aldehydes afford 2-amino-1,3,4-oxadiazole derivatives.The 2,4-disubstituted semicarbazones give 2,4-dihydro-1,2,4-triazo
- Nguyen, Thu-Huong,Milcent, Rene,Barbier, Geo
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p. 1383 - 1388
(2007/10/02)
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