158325-89-4Relevant academic research and scientific papers
ARYL-PHENYL-SULFONAMIDE-PHENYLENE COMPOUNDS AND THEIR USE
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Page/Page column 100, (2010/04/25)
The present invention pertains generally to the field of therapeutic compounds, and more specifically to certain aryl-phenyl-sulfonamido-phenylene compounds of the following formula (I) (collectively referred to herein as "APSAP compounds"). The present invention also pertains to pharmaceutical compositions comprising such compounds, and the use of such compounds and compositions, both in vitro and in vivo, in treatment, for example, of inflammation and/or joint destruction and/or bone loss; of disorders mediated by excessive and/or inappropriate and/or prolonged activation of the immune system; of inflammatory and autoimmune disorders, for example, rheumatoid arthritis, psoriasis, psoriatic arthritis, chronic obstructive pulmonary disease (COPD), atherosclerosis, inflammatory bowel disease, ankylosing spondylitis, and the like; of disorders associated with bone loss, such as bone loss associated with excessive osteoclast activity in rheumatoid arthritis, osteoporosis, cancer-associated bone disease, Paget's disease and the like, etc.; and of cancer, such as a haematological malignancy, a solid tumour, etc.
Asymmetric synthesis of conformationally restricted L-arginine analogues as active site probes of nitric oxide synthase
Atkinson,Moore,Tobin,King
, p. 3467 - 3475 (2007/10/03)
Using the catalytic asymmetric sharpless carbamate aminohydroxylation, conformationally restricted L-arginine and L-homoarginine derivatives (5-8) were prepared in good enantiomeric excess to investigate the binding requirements of L-arginine-based compounds with nitric oxide synthase. The L- arginine derivatives (5 and 6) inhibited both the inducible and neuronal isoforms of nitric oxide synthase with little isoform selectivity (5, IC50 = 42 and 144 μM, 6, 8 and 12 μM, respectively). The guanidine-containing compound (5) did not act as a nitric oxide producing substrate for nitric oxide synthase. The ability of these compounds to interact with the enzyme supports the idea that L-arginine-based inhibitors bind to the enzyme in a folded conformation. The L-homoarginine derivatives (7 and 8) did not interact with the enzyme as either substrates or inhibitors. The two-carbon L-arginine homologue (9), prepared from L-phenylalanine, demonstrated the greatest isoform selective inhibition of the compounds examined (IC50(iNOS) = 19 and IC50(nNOS) = 147 μM, IC50(nNOS)/IC50i(NOS) = 7.7). These results suggest isoform selective inhibition may be related to the folded conformations required for binding of these higher L-arginine homologues.
