1391007-38-7Relevant academic research and scientific papers
Identification of Cyanamide-Based Janus Kinase 3 (JAK3) Covalent Inhibitors
Casimiro-Garcia, Agustin,Trujillo, John I.,Vajdos, Felix,Juba, Brian,Banker, Mary Ellen,Aulabaugh, Ann,Balbo, Paul,Bauman, Jonathan,Chrencik, Jill,Coe, Jotham W.,Czerwinski, Robert,Dowty, Martin,Knafels, John D.,Kwon, Soojin,Leung, Louis,Liang, Sidney,Robinson, Ralph P.,Telliez, Jean-Baptiste,Unwalla, Ray,Yang, Xin,Thorarensen, Atli
, p. 10665 - 10699 (2019/01/03)
Ongoing interest in the discovery of selective JAK3 inhibitors led us to design novel covalent inhibitors that engage the JAK3 residue Cys909 by cyanamide, a structurally and mechanistically differentiated electrophile from other cysteine reacting groups previously incorporated in JAK3 covalent inhibitors. Through crystallography, kinetic, and computational studies, interaction of cyanamide 12 with Cys909 was optimized leading to potent and selective JAK3 inhibitors as exemplified by 32. In relevant cell-based assays and in agreement with previous results from this group, 32 demonstrated that selective inhibition of JAK3 is sufficient to drive JAK1/JAK3-mediated cellular responses. The contribution from extrahepatic processes to the clearance of cyanamide-based covalent inhibitors was also characterized using metabolic and pharmacokinetic data for 12. This work also gave key insights into a productive approach to decrease glutathione/glutathione S-transferase-mediated clearance, a challenge typically encountered during the discovery of covalent kinase inhibitors.
Synthesis of α,α-difluoroethyl aryl and heteroaryl ethers
Yang, Eddie,Reese, Matthew R.,Humphrey, John M.
supporting information; experimental part, p. 3944 - 3947 (2012/09/21)
Fluorine plays a critical role in modern medicinal chemistry due to its unique properties, and new methods for its incorporation into target molecules are of high interest. An efficient new method for the preparation of aryl-α,α-difluoroethyl ethers (4) via addition of aryl and heteroaryl alcohols (1) to commercially available 2-bromo-1,1-difluoroethene (2) and subsequent hydrogenolysis is presented. This procedure is an attractive alternative to existing methods that employ harshly reactive fluorinating systems such as xenon difluoride and hydrogen fluoride.
