- POTENT AND HIGHLY SELECTIVE HETEROAROMATIC INHIBITORS OF NEURONAL NITRIC OXIDE SYNTHASE
-
Peptidomimetic compounds as can inhibit neuronal nitric oxide synthase (nNOS) for potential treatment in neurodegenerative diseases, such as but not limited to stroke, Alzheimer's disease, Parkinson's disease, Huntington's disease.
- -
-
-
- Minimal pharmacophoric elements and fragment hopping, an approach directed at molecular diversity and isozyme selectivity. Design of selective neuronal nitric oxide synthase inhibitors
-
Fragment hopping, a new fragment-based approach for de novo inhibitor design focusing on ligand diversity and isozyme selectivity, is described. The core of this approach is the derivation of the minimal pharmacophoric element for each pharmacophore. Sites for both ligand binding and isozyme selectivity are considered in deriving the minimal pharmacophoric elements. Five general-purpose libraries are established: the basic fragment library, the bioisostere library, the rules for metabolic stability, the toxicophore library, and the side chain library. These libraries are employed to generate focused fragment libraries to match the minimal pharmacophoric elements for each pharmacophore and then to link the fragment to the desired molecule. This method was successfully applied to neuronal nitric oxide synthase (nNOS), which is implicated in stroke and neurodegenerative diseases. Starting with the nitroarginine-containing dipeptide inhibitors we developed previously, a small organic molecule with a totally different chemical structure was designed, which showed nanomolar nNOS inhibitory potency and more than 1000-fold nNOS selectivity. The crystallographic analysis confirms that the small organic molecule with a constrained conformation can exactly mimic the mode of action of the dipeptide nNOS inhibitors. Therefore, a new peptidomimetic strategy, referred to as fragment hopping, which creates small organic molecules that mimic the biological function of peptides by a pharmacophore-driven strategy for fragment-based de novo design, has been established as a new type of fragment-based inhibitor design. As an open system, the newly established approach efficiently incorporates the concept of early "ADME/Tox" considerations and provides a basic platform for medicinal chemistry-driven efforts.
- Ji, Haitao,Stanton, Benjamin Z.,Igarashi, Jotaro,Li, Huiying,Martasek, Pavel,Roman, Linda J.,Poulos, Thomas L.,Silverman, Richard B.
-
p. 3900 - 3914
(2008/12/20)
-
- HETEROAROMATIC SELECTIVE INHIBITORS OF NEURONAL NITRIC OXIDE SYNTHASE
-
Compounds inhibiting neuronal nitric oxide synthase (nNOS) for potential treatment in neurodegenerative diseases, such as stroke, Alzheimer's disease, Parkinson's disease, Huntington's disease, such compounds of a formula.
- -
-
Page/Page column 20
(2008/06/13)
-
- Pyrimidine derivatives as IL-8 receptor antagonists
-
Compounds containing the pyrimidine nucleus and their use to treat diseases and conditions related to inappropriate Interleukin-8 receptor activity are disclosed. The compounds are of the formula I In these compounds, Q is preferably unsubstituted and substituted heterocyclyl; U is usually hydrogen or fluorine; and V is preferably hydrogen, halogen, alkyl, —O—alkyl or —S-alkyl. A representative example is:
- -
-
-
- New route to 4-aminocyclopent-2-en-1-ols: Synthesis and enantioselective rearrangement of 4-amino-substituted cyclopentene oxides
-
A new route for the asymmetric synthesis of 4-aminocyclopent-2-en-1-ols (90% ee) for carbocyclic nucleoside analogue synthesis is described. The approach involves the stereoselective preparation of cis 4-amino-substituted cyclopentene oxides and subsequent chiral base-mediated rearrangement to the corresponding allylic alcohols. Full details on the synthesis and stereoselectivity of epoxidation of 4-amino-substituted cyclopentenes are presented. (C) 2000 Elsevier Science Ltd.
- Barrett, Stephen,O'Brien, Peter,Steffens, H.Christian,Towers, Timothy D,Voith, Matthias
-
p. 9633 - 9640
(2007/10/03)
-
- 2-amino-5,6-dichlorobenzimidazole derivatives having antiviral activity
-
The present invention relates to benzimidazole derivatives of formula (I) wherein: R1 represents H, C1-4 alkyl, C3-5 cycloalkyl; R2 represents H, C1-4 alkyl; or R1 and R2 together form with the nitrogen a 4 or 5 membered heterocyclic ring; R3 represents BR4 or R4 wherein B represents a bridging group --C(O)NH--, --C(O)NC1-4 alkyl-, or C(O)O-- and R4 represents H, C1-4 alkyl, C2-6 alkenyl or halo (preferably fluoro); and each n is an integer independently selected from 0, 1, or 2 (preferably 0 or 1); and geometric isomers or mixtures thereof; and physiologically functional derivatives thereof, and their use in medical therapy particularly for the treatment or prophylaxis of virus infections such as those caused by herpes viruses. The invention also relates to their preparation and pharmaceutical formulations containing them.
- -
-
-
- On the possibility of carbamate-directed hydroboration. An approach to the asymmetric synthesis of 1-aminocyclopentane-1,3-dicarboxylic acid
-
Hydroboration (using BH3) of 1-substituted 3-cyclopentenes 3, 9 and 17 and an enantioselective synthesis of the excitatory amino acid 1- aminocyclopentane-1,3-dicarboxylic acid via asymmetric hydroboration [90% de, 45% ee using (+)-IpcBH2] of cyclopentene 17 are described.
- Hodgson, David M.,Thompson, Alison J.,Wadman, Sjoerd,Keats, Clare J.
-
p. 10815 - 10834
(2007/10/03)
-
- Synthesis and enantioselective rearrangement of 4-amino-substituted cyclopentene oxides
-
Several N-mono- and diprotected alkenes have been prepared and the stereoselectivity of their epoxidation has been investigated: N-monoprotected alkenes give cis epoxides preferentially (due to hydrogen bonding directed epoxidations) whereas N-diprotected alkenes produce trans epoxides exclusively (due to steric effects). Chiral lithium amide base-mediated rearrangement of a cis-monoprotected epoxide generated the corresponding amino-cyclopentenol in good yield and with an enantiomeric excess of 60%.
- O'Brien, Peter,Towers, Timothy D.,Voith, Matthias
-
p. 8175 - 8178
(2007/10/03)
-
- Carbamate-directed hydroboration: Enantioselective synthesis of the excitatory amino acid 1-aminocyclopentane-1,3-dicarboxylic acid
-
Carbamate-directed hydroboration (using BH3) of 1-substituted 3- cyclopentenes 2, 6 and 9 and an enantioselective synthesis of the excitatory amine acid 1-aminocyclopentane-1,3-dicarboxylic acid via carbamate-directed asymmetric hydroboration [90% de, 45% ee using (+)-IpcBH2] of cyclopentene 2 are described.
- Hodgson, David M.,Thompson, Alison J.,Wadman, Sjoerd
-
p. 3357 - 3358
(2007/10/03)
-
