862168-15-8Relevant academic research and scientific papers
Fragment-based drug discovery applied to Hsp90. Discovery of two lead series with high ligand efficiency
Murray, Christopher W.,Carr, Maria G.,Callaghan, Owen,Chessari, Gianni,Congreve, Miles,Cowan, Suzanna,Coyle, Joseph E.,Downham, Robert,Figueroa, Eva,Frederickson, Martyn,Graham, Brent,McMenamin, Rachel,O'Brien, M. Alistair,Patel, Sahil,Phillips, Theresa R.,Williams, Glyn,Woodhead, Andrew J.,Woolford, Alison J.-A.
supporting information; experimental part, p. 5942 - 5955 (2010/11/04)
Inhibitors of the chaperone Hsp90 are potentially useful as chemotherapeutic agents in cancer. This paper describes an application of fragment screening to Hsp90 using a combination of NMR and high throughput X-ray crystallography. The screening identified an aminopyrimidine with affinity in the high micromolar range and subsequent structure-based design allowed its optimization into a low nanomolar series with good ligand efficiency. A phenolic chemotype was also identified in fragment screening and was found to bind with affinity close to 1 mM. This fragment was optimized using structure based design into a resorcinol lead which has subnanomolar affinity for Hsp90, excellent cell potency, and good ligand efficiency. This fragment to lead campaign improved affinity for Hsp90 by over 1000000-fold with the addition of only six heavy atoms. The companion paper (DOI: 10.1021/jm100060b) describes how the resorcinol lead was optimized into a compound that is now in clinical trials for the treatment of cancer.
2-(2-Furanyl)-7-phenyl[1,2,4]triazolo[1,5-c]pyrimidin-5-amine analogs: Highly potent, orally active, adenosine A2A antagonists. Part 1
Matasi, Julius J.,Caldwell, John P.,Zhang, Hongtao,Fawzi, Ahmad,Cohen-Williams, Mary E.,Varty, Geoffrey B.,Tulshian, Deen B.
, p. 3670 - 3674 (2007/10/03)
The structure-activity relationship of this novel class of compounds based on 2-(2-furanyl)-7-phenyl[1,2,4]-triazolo[1,5-c]pyrimidin-5-amine, 1, and its analogs was evaluated for their in vitro and in vivo adenosine A2A receptor antagonism. Several compounds displayed oral activity at 3 mg/kg in a rat catalepsy model. Specifically, compound 8g displayed an excellent in vitro profile, as well as a highly promising in vivo profile.
