Drug design and discovery最新文献

Pharmacophore/receptor models for 6 recombinant GABA(A)/BzR subtypes (alphax beta3gamma2, x = 1-6) have been established via an SAR ligand mapping approach. This study was based on the affinities of 166 BzR ligands at 6 distinct (alpha1-6beta3gamma2) recombinant GABA(A)/BzR receptor subtypes from at least twelve different structural families. Examination of the included volumes indicated that the shapes of binding pockets for alpha1, alpha2 and alpha3 subtypes are very similar to each other. Region L2 for the alpha5 containing subtype appeared to be larger in size than the analogous region of the other receptor subtypes. Region L(Di), in contrast, appeared to be larger in the alpha1 subtype than in the other subtypes. Moreover, region L3 in the alpha6 subtype is either very small or nonexistent in this diazepam insensitive "DI" subtype as compared to the other subtypes. Preliminary results for the alpha4-containing receptor subtype (DI) indicate that L3 in the alpha4 subtype suffers a similar fate. Use of the pharmacophore/receptor models for these subtypes have resulted in the design of novel BzR ligands selective for the alpha5beta3gamma2, receptor subtype.

A series of 3-phenylsulfonylquinazoline-2,4-dione derivatives have been synthesized and evaluated for their ability to inhibit human heart chymase. The structure-activity relationship studies on these compounds gave the following results. The phenyl moiety of quinazoline participates in a hydrophobic interaction where an optimum size is required. In this moiety, 7-chloroquinazoline is the best moiety for inhibiting chymase, chymotrypsin and cathepsin G. A 3-phenylsulfonyl moiety substituted with hydrophobic electron-withdrawing groups at the 4-position potentiated the activity. Anthranil moiety also enhanced the activity. Pyridylmethyl and N-pyridylacetamide at the 1-position gave an IC50 in the order of 10(-8)M. Molecular modeling studies on the interaction of 7-chloro-3-(4-chlorophenylsulfonyl) quinazoline-2,4(1H, 3H)-dione (4) with the active site of human heart chymase suggested that the phenyl moiety of quinazoline interacts with the hydrophobic P1 pocket, the 3-phenylsulfonyl moiety resides in the S1'-S2' subsites, the moiety at the 1-position locates in the S2-S3 subsites and the 4-carbonyl and 3-sulfonyl group interact with the oxyanion hole and the His57 side-chain of chymase, respectively.

Several novel N-type voltage sensitive calcium channel blockers showed high affinity in the IMR32 assay and efficacy in the anti-writhing model. Herein, we describe the design, synthesis, SAR studies, biological data, physicochemical properties and pharmacokinetics of this 4-piperidinylaniline series.

The conformational characteristics responsible for high affinity mu-opioid binding of a series of fentanyl analogs have been investigated using a combination of molecular mechanics and molecular dynamics techniques. In general, the fentanyl analogs favor a conformation that is quite different in gas phase, and in the presence of explicit solvent or lattice packing forces. The most active analogs were shown to possess an extended conformation, while fentanyl derivatives displaying reduced binding affinities are predicted to favor compact arrangements. A superposition of the proposed "bioactive conformations" across this ligand series identified the orientation of the N-phenethyl and the N-phenyl group to be a contributing factor responsible for the differential binding of the ohmefentanyl enantiomers, and other structural analogs. The proposed 3-point pharmacophore model for the fentanyls also provide insights into the structure-activity relationship and serve as a template for further QSAR and docking studies.

Exploration of the SAR around the leucine side chain in a series of N,N-dialkyldipeptidylamines with potent functional activity at N-type VSCC is presented. A novel analog is disclosed which possesses improved aqueous solubility, in vivo activity in an audiogenic seizure model, and reversible blockade in electrophysiological assays.

A series of 4-(N,N-diarylamino)piperidines are synthesized and evaluated for high affinity binding and selectivity to the delta-opioid receptor using a combination of 3D-QSAR and molecular docking techniques. Based on experimental ligand binding data to both mu- and delta- opioid receptors, CoMFA fields are generated and applied to identify potential ligand modifications to further optimize lead compounds. Molecular docking experiments to the delta-receptor are also reported that explain the CoMFA trends predicted as well as the differential binding and selectivity displayed by various compounds in the series. An analysis of the binding site model proposed indicates the piperidines take advantage of 3 key sites or binding domains within the delta-receptor. These include an aromatic pocket (approximately 1/3 into the receptor cavity), an aspartic acid residue (which serves as a docking point for the piperidinyl cationic amine) and a hydrophobic pocket at the extracellular boundary of the receptor cavity. Links are established between ligand modification and amino acid composition at these sites in mu and delta, providing new insight to the structural basis to binding and selectivity across the series and for related piperazines (i.e. SNC80 and BW373U86). Results are also presented that indicate delta- and mu-selectivity may be determined at alternate sites, suggesting opioid receptors may display multiple binding domains. The model is further supported by comparisons with opiate binding modes and site directed mutagenesis studies and is finally applied to suggest new strategies in ligand design.

Knowledge and Knowledge Management are becoming common senior management parlance in the Pharmaceutical Industry in the late 1990s. This perspective article will address exactly what is knowledge and the various techniques available to harness and use it to drive the pharmaceutical business process. The impact of knowledge on this process to provide a better service to the industry's customers (the patient) are discussed with respect to the key business problems facing the industry as it enters the new millennium.

The binding of beta 2glycoprotein I (beta 2GPI) to anionic phospholipids (PL) leads to the presentation of one or more epitopes recognized by autoantibodies from patients with antiphospholipid syndrome (APS). The inhibition of beta 2GPI binding to PL mixtures coated on polystyrene microtiter wells (MTW) and to large, multilamellar PL vesicles (LMV) was examined. Inhibitors included phosphorylated monosaccharide metabolites, myo-inositol monophosphate (IMP), hexaphosphate (IHP) and hexasulfate (IHS), pyrophosphate (PPi), methyl bisphosphonate (MBP) and phenyl phosphonate, and a series of carboxylic and aromatic sulfonic acids. Inhibitors were incubated with beta 2GPI at 37 degrees C for 2 hr either with dimyristoylphosphatidic acid, 80%/dimyristoylphosphatidyl choline, 20% (DMPA/DMPC) coated on MTW or in a suspension of LMV. Phospholipid-bound beta 2GPI to PA/PC on MTW was detected using an immunoassay based on rabbit anti-beta 2GPI; free beta 2GPI (not bound to LMV) was detected by fluorescence spectroscopy. Inhibition was studied over the range 0.01-9.0 mumoles/10(-4)L (0.1-90 mM). Inhibition at maximum concentration in the MTW system ranged from 0.1% (for ADP) to > 94% (for IHP). IHP also provided the greatest inhibition in the LMV system (76%) and was also effective in displacing beta 2GPI already bound to PL surfaces (approximately 50% displaced at 0.25 mM). These data suggest that a strategy for development of therapeutic agents for APS may be based on the use of small cyclic, organic oligoanions such as inositol derivatives to act as ligands for lysine residues at the PL binding site of beta 2GPI.

Starting from furfural, 5-hydroxy-3,4-dihalo-2(5H)-furanones and 5-hydroxy-4 chloro-2(5H)-furanone were converted into 3 sublibraries of halogenated 5-alkoxy-2(5H)-furanones. The reactivity of 24 halogenated 5-alkoxy2(5H)-furanones was chemically evaluated by using 4 selected amines for subsequent reactions. The biological evaluation of the pseudo-muco halogen esters resulted in the discovery of a lead structure with potent anti-cancer activity.