283173-83-1Relevant academic research and scientific papers
Discovery of GSK251: A Highly Potent, Highly Selective, Orally Bioavailable Inhibitor of PI3Kδ with a Novel Binding Mode
Down, Kenneth,Amour, Augustin,Anderson, Niall A.,Barton, Nick,Campos, Sebastien,Cannons, Edward P.,Clissold, Cole,Convery, Maire A.,Coward, John J.,Doyle, Kevin,Duempelfeld, Birgit,Edwards, Christopher D.,Goldsmith, Michael D.,Krause, Jana,Mallett, David N.,McGonagle, Grant A.,Patel, Vipulkumar K.,Rowedder, James,Rowland, Paul,Sharpe, Andrew,Sriskantharajah, Srividya,Thomas, Daniel A.,Thomson, Douglas W.,Uddin, Sorif,Hamblin, J. Nicole,Hessel, Edith M.
supporting information, p. 13780 - 13792 (2021/09/28)
Optimization of a previously reported lead series of PI3Kδ inhibitors with a novel binding mode led to the identification of a clinical candidate compound 31 (GSK251). Removal of an embedded Ames-positive heteroaromatic amine by reversing a sulfonamide followed by locating an interaction with Trp760 led to a highly selective compound 9 . Further optimization to avoid glutathione trapping, to enhance potency and selectivity, and to optimize an oral pharmacokinetic profile led to the discovery of compound 31 (GSK215) that had a low predicted daily dose (45 mg, b.i.d) and a rat toxicity profile suitable for further development.
CHEMICAL COMPOUNDS AS INHIBITORS OF KINASE ACTIVITY
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Page/Page column 88-89, (2017/09/05)
The invention is directed to certain novel compounds. Specifically, the invention is directed to compounds of formula (I): (I) and salts thereof. The compounds of the invention are inhibitors of kinase activity, in particular PI3- kinase activity.
Discovery of two clinical histamine H3 receptor antagonists: Trans - N -ethyl-3-fluoro-3-[3-fluoro-4-(pyrrolidinylmethyl)phenyl] cyclobutanecarboxamide (PF-03654746) and trans -3-fluoro-3-[3-fluoro-4- (pyrrolidin-1-ylmethyl)phenyl]- N -(2-methy
Wager, Travis T.,Pettersen, Betty A.,Schmidt, Anne W.,Spracklin, Douglas K.,Mente, Scot,Butler, Todd W.,Howard, Harry,Lettiere, Daniel J.,Rubitski, David M.,Wong, Diane F.,Nedza, Frank M.,Nelson, Frederick R.,Rollema, Hans,Raggon, Jeffrey W.,Aubrecht, Jiri,Freeman, Jody K.,Marcek, John M.,Cianfrogna, Julie,Cook, Karen W.,James, Larry C.,Chatman, Linda A.,Iredale, Philip A.,Banker, Michael J.,Homiski, Michael L.,Munzner, Jennifer B.,Chandrasekaran, Rama Y.
experimental part, p. 7602 - 7620 (2012/01/05)
The discovery of two histamine H3 antagonist clinical candidates is disclosed. The pathway to identification of the two clinical candidates, 6 (PF-03654746) and 7 (PF-03654764) required five hypothesis driven design cycles. The key to success i
HISTAMINE-3 RECEPTOR ANTAGONISTS
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Page/Page column 34-35, (2010/11/27)
This invention is directed to a compound of formula Ias defined herein, or a pharmaceutically acceptable salt thereof; a pharmaceutical composition containing a compound of formula I, a process of preparation of a compound of formula I, a method of treatment of a disorder or condition that may be treated by antagonizing histamine H3 receptors, the method comprising administering to a mammal in need of such treatment a compound of formula I as described above, and a method of treatment of a disorder or condition selected from the group consisting of depression, mood disorders, schizophrenia, anxiety disorders, Alzheimer's disease, attention-deficit hyperactivity disorder (ADHD), psychotic disorders, cognitive disorders, sleep disorders, obesity, dizziness, epilepsy, motion sickness, respiratory diseases, allergy, allergy- induced airway responses, allergic rhinitis, nasal congestion, allergic congestion, congestion, hypotension, cardiovascular disease, diseases of the GI tract, hyper and hypo motility and acidic secretion of the gastro- intestinal tract, the method comprising administering to a mammal in need of such treatment a compound of formula I as described above.
