64834-59-9Relevant academic research and scientific papers
Discovery of highly potent and selective inhibitors of neuronal nitric oxide synthase by fragment hopping
Ji, Haitao,Li, Huiying,Martásek, Pavel,Roman, Linda J.,Poulos, Thomas L.,Silverman, Richard B.
experimental part, p. 779 - 797 (2009/12/07)
Selective inhibition of neuronal nitric oxide synthase (nNOS) has been shown to prevent brain injury and is important for the treatment of various neurodegenerative disorders. This study shows that not only greater inhibitory potency and isozyme selectivity but more druglike properties can be achieved by fragment hopping. On the basis of the structure of lead molecule 6, fragment hopping effectively extracted the minimal pharmacophoric elements in the active site of nNOS for ligand hydrophobic and steric interactions and generated appropriate lipophilic fragments for lead optimization. More potent and selective inhibitors with better druglike properties were obtained within the design of 20 derivatives (compounds 7-26). Our structure - based inhibitor design for nNOS and SAR analysis reveal the robustness and efficiency of fragment hopping in lead discovery and structural optimization, which implicates a broad application of this approach to many other therapeutic targets for which known druglike small-molecule modulators are still limited.
Novel pyrrolidine ureas as C-C chemokine receptor 1 (CCR1) antagonists
Merritt, J. Robert,Liu, Jinqi,Quadros, Elizabeth,Morris, Michelle L.,Liu, Ruiyan,Zhang, Rui,Jacob, Biji,Postelnek, Jennifer,Hicks, Catherine M.,Chen, Weiqing,Kimble, Earl F.,Rogers, W. Lynn,O'Brien, Linda,White, Nicole,Desai, Hema,Bansal, Shalini,King, George,Ohlmeyer, Michael J.,Appell, Kenneth C.,Webb, Maria L.
supporting information; experimental part, p. 1295 - 1301 (2009/12/07)
Monocyte infiltration is implicated in a variety of diseases including multiple myeloma, rheumatoid arthritis, and multiple sclerosis. C-C chemokine receptor 1 (CCR1) is a chemokine receptor that upon stimulation, particularly by macrophage inflammatory protein 1a (MIP-1a) and regulated on normal T-cell expressed and secreted (RANTES), mediates monocyte trafficking to sites of inflammation. High throughput screening of our combinatorial collection identified a novel, moderately potent CCR1 antagonist 3. The library hit 3 was optimized to the advanced lead compound 4. Compound 4 inhibited CCR1 mediated chemotaxis of monocytes with an IC50 of 20 nM. In addition, the compound was highly selective over other chemokine receptors. It had good microsomal stability when incubated with rat and human liver microsomes and showed no significant cytochrome P450 (CYP) inhibition. Pharmacokinetic evaluation of the compound in the rat showed good oral bioavailability.
Synthesis of N-substituted oxazolidines and morpholines
Magerramov,Magerramov,Makhmudova,Alizade
, p. 1301 - 1305 (2007/10/03)
A series of N-substituted oxazolidines and morpholines were prepared and characterized.
Structural studies on bioactive compounds. 34.1 Design, synthesis, and biological evaluation of triazenyl-substituted pyrimethamine inhibitors of Pneumocystis carinii dihydrofolate reductase
Chan,Laughton,Queener,Stevens
, p. 2555 - 2564 (2007/10/03)
The triazenyl-pyrimethamine derivative 3a (TAB), a potent and selective inhibitor of Pneumocystis carinii DHFR, was selected as the starting point for a lead optimization study. Molecular modeling studies, corroborated by a recent crystal structure determination of the ternary complex of P. carinii DHFR-NADPH bound to TAB, predicted that modifications to the acetoxy residue of the lead inhibitor could exploit binding opportunities in the vicinity of an active site pocket bounded by residues Ile33, Lys37, and Leu72. Substitutions in the benzyl moiety with electron-donating and electron-withdrawing groups were predicted to probe face-edge interactions with amino acid Phe69 unique to the P. carinii enzyme. New triazenes 10a-v and 12a-f were prepared by coupling the diazonium tetrafluoroborate salt 6b of aminopyrimethamine with substituted benzylamines or phenethylamines. The most potent of the new inhibitors against P. carinii DHFR was the naphthylmethyl-substituted triazene 10t (IC50: 0.053 μM), but a more substantial increase in potency against the rat liver DHFR led to a reduction in selectivity (ratio rat liver DHFR IC50/P. carinii DHFR IC50: 5.36) compared to the original lead structure 3a (ratio rat liver DHFR IC50/P. carinii DHFR IC50: 114).
