Drug design and discovery最新文献

Several thiazolyl derivatives are reported to act as lipoxygenase inhibitors affecting inflammation and/or psoriasis. Two series of new thiazolyl and benzothiazolyl Schiff bases have been designed, synthesized and identified. RM values were determined as an expression of lipophilicity. The compounds were screened for their reducing activity (with the stable free radical 1,1-diphenyl-2-picrylhydrazyl DPPH), for radical scavenging activity (with the xanthine/xanthine oxidase system for O2.-) and for inhibition of soybean lipoxygenase (LO). Anti inflammatory activity was examined in vivo, using the carrageenin induced mice paw edema (24-71.8% inhibition was observed). The results are discussed in terms of structural and physicochemical characteristics of the compounds. Comparing the results among all tests, the benzothiazolyl derivatives seem to be more potent.

Tetra-O-acetylgalactopyranosylamine and tetra-O-acetylglucopyranosylamine of D-Met2, Pro5 enkephalin were designed and synthesized to enhance their membrane penetration, biological activity and resistance to proteolytic hydrolysis. Three approaches to the synthesis were attempted, which lead to a new synthetic scheme with a higher yield and enhanced ease of purification. The improved procedure involved attaching the tetra-O-acetylglycopyranosylamine to a t-Boc-Gly-Phe-Pro-OH peptide, removing the t-Boc, and condensing it with t-Boc-Tyr-D-Met-OH. Biological evaluation in vivo showed that these acetylglycopyranosylamine derivatives bind to mu and delta opioid receptors in homogenate binding assays and possess analgesic activity. The analgesic potency was less than that of the parent compound D-Met2, Pro5 enkephalin. These acetylglycopyranosylamine derivatives showed enhanced lipophilicity compared to their parent compound by a partition coefficient study and they also showed greater membrane permeability, using the rabbit cornea as a model system. These derivatives also are resistant to hydrolytic enzymes as compared to the endogenous met-enkephalin when evaluated in homogenized iris-ciliary body and aqueous humor from rabbit eyes.

A series of substituted indenopyridazinones (4b-h) has been synthesized and tested for their antisecretory and antiulcer activity, in comparison with ranitidine, as reference drug. While the monomethoxy (4b-d), as well as the benzyloxy (4f) and the 6,9-dimethoxy (4g) derivatives were found to be devoid of overt antisecretory properties, the 9-methoxy (4e) was weakly active. The most interesting compound of this class was the 7,8-dimethoxy substituted (4h), which at an oral dose of 30 mg/kg still retains a significant activity. The dihydroderivatives of 4g,h (compounds 1g,h) were more active (1g) or comparable (1h) to the parent compounds, thus proving that the 4, 4a-double bond, which was an essential requirement in the analogues 2 and 3, is not necessary in this new series. The disubstituted derivatives (1g,h; 4g,h) were also tested as antiulcer agents, in two different models. All compounds were able to prevent haemorragic lesions induced in rats by 90% ethanol in a dose dependent manner. In the indomethacin model they still showed a significant activity, though lower than in the previous test. Attempts have been made to elucidate their mechanism of action.

This study is an attempt to incorporate the butyrophenones, an important class of nontricyclic antipsychotic drugs, into a previously proposed pharmacophore model of tricyclic dopamine D2 receptor antagonist ligands. Conformational energy calculations were performed using the MM3-92 program on spiperone, as a representative butyrophenone, and milenperone and R48455, as related compounds with more limited conformational freedom. Twenty seven conformers were evaluated for spiperone with MM3-92 calculations and nine of these were within 1.1 kcal/mole of the global minima indicating the flexibility of the compound. A conformational analysis of twenty crystal structures of butyrophenones was also performed and six distinct conformers were represented. All of the energy minimized conformers of spiperone were superimposed in a least squares sense onto loxapine as a relatively rigid, typical D2 antagonist and a pair of mirror image conformers, which are observed in one crystal structure of spiperone, were found to be the best fit. However, it was not possible to discriminate between these two conformers since they fit the pharmacophore model equally well. The para-fluoro and carbonyl group of the butyrophenones were found to correspond best to the oxygen and chlorine atoms of loxapine, respectively. The conformations of milenperone and R48455 were also consistent with the two putative biologically active forms of spiperone and the pharmacophore model. Conformational energy calculations were also performed on molindone, an antipsychotic drug in clinical use, which can be related to the butyrophenones since both have a carbonyl group adjacent to an aromatic ring. A putative biologically active form was proposed for molindone and this was related to the structure of piquindone, a rigid analog of molindone. All of the compounds were found to be entirely consistent with the pharmacophore model. However, as previously found, there is great variability in the distance between the ammonium nitrogen and the center of the relevant aromatic ring with the most extreme case in the present study being R48455 where the distance is 7.2 A. The results of the present study should also be relevant to the structures of novel, atypical antipsychotic drugs such as risperidone which appear to be analogs of the butyrophenones.

Novel ketomethoxime (BMO) and oxime (BO) analogs of betaxolol (B) were prepared through the oxidation of betaxolol, followed by quenching of the ketone with the appropriate oxyamine. The Z isomers were kinetically favored and thermodynamically more stable. Isomerization to reach an equilibrium mixture of Z/E was observed for all pure isomers in buffers. Equilibration is much faster, however in biological fluids. Ocular administration of any of the oxime derivatives, delivers betaxolol specifically to the eye tissues, with the highest concentration in the iris ciliary body. Both BMO and BO, when applied topically, showed marked reduction of intraocular pressure (IOP) in normotensive rabbits. No effect on isoproterenol-induced tachycardia in rabbits and rats were observed, even after iv. administration. Very mild eye irritation, which was less than that of betaxolol hydrochloride, was observed particularly with BMO maleate, which is an excellent candidate for safe treatment of glaucoma.

The present study describes the synthesis and quantitative structure activity relationships (QSAR) of novel 3-amino-2-(substituted)aminomethyl-5,6-disubstitutedthieno[2,3-d] pyrimidin-4(3H)-ones for their potent H1-receptor antagonist activity on the guinea pig ileum. With the IC50 values in the range of 10(-5) gms/lit, all the compounds tested were found to possess ten fold higher affinity to the H1-receptor than diphenhydramine and cetirizine, but lower than astemizole and loratidine. The sedative potential of these compounds was found to be lower than cetirizine and astemizole but comparable to loratidine. The QSAR study indicates a parabolic relationship of the biological activity mainly with the steric parameters and partly with the lipophilic parameters.

An essential step in the replication of retroviruses is the integration of a DNA copy of the viral genome into the genome of the host cell. Integration encompasses a series of ordered endonucleolytic and DNA strand transfer reactions catalyzed by the viral enzyme, integrase. The requirement for integrase activity in the propagation of HIV-1 in cell culture defines the enzyme as a potential target for chemotherapeutic intervention. We have therefore developed a non-radioisotopic microtiter plate assay which can be used to identify novel inhibitors of integrase from random chemical screens and for the bioassay driven isolation of inhibitors from natural products. This assay uncouples various steps in the reaction pathway and therefore can be exploited to characterize inhibitors. In this monograph we describe a series of modifications to the method which facilitate such mechanistic studies using as an example a series of previously described integrase inhibitors.

The herpesvirus protease is a recently identified enzyme which is essential for viral replication. It is found in all herpesviruses and offers a new molecular target for therapeutic intervention. Its genomic structure has recently been described and consists of a large open reading frame which encodes a fusion protein containing an amino-terminal protease domain in-frame with a carboxyl-terminal "assembly protein-like" domain. Auto-processing releases the amino-terminal protease as a maturational enzyme. The herpesvirus protease has been characterized as a novel serine protease. Four surface accessible sulfhydryl groups have been identified in the human cytomegalovirus (HCMV) protease. Utilizing a fluorogenic DABCYL-EDANS substrate assay, directed screening has identified a class of sulfhydryl-modifying benzimidazolylmethyl sulfoxides which inhibits recombinant HCMV protease. Site-directed mutagenesis studies suggest oxidative modification of surface-accessible HCMV protease Cys138 (and possibly Cys161) by this class of inhibitors. The benzimidazolylmethyl sulfoxide 1 inhibits HCMV protease (IC50 = 1.9 microM), exhibits selectivity vs. mammalian serine proteases, and exhibits antiviral activity in an HCMV infected cell culture assay.

Novel antiherpetic 3-quinolinecarboxamides were discovered as part of a drug discovery program at Sterling Winthrop Inc. A major goal of this research was to identify novel non-nucleoside agents possessing activity against acyclovir resistant herpes simplex virus. From screening compound libraries in an HSV-2 plaque reduction assay, 1-ethyl-1,4-dihydro-4-oxo-7-(4-pyridinyl)-3-quinolinecarboxamide (1) emerged as an attractive lead structure. By modifying the quinoline ring at the 1-, 2-, 3-, 4-, and 7-positions, analogues were identified that have up to 5-fold increased in vitro potency relative to acyclovir. In a single dose mouse model of infection the 1-(4-FC6H4) analogue 17, one of the most potent derivatives in vitro, displayed comparable oral antiherpetic efficacy to acyclovir at 1/16 the dose; in a multiple dose regimen, however, it was 2-fold less potent. Mechanism of action studies indicate that these new compounds interact with a different, as yet undefined, molecular target than acyclovir.

Substituted 2,2'-dithiobisbenzamides and 2-benzisothiazolones were prepared and shown to possess low microM activity with high therapeutic indices against HIV-1, HIV-2 and SIV in cell culture. The mechanism of antiviral action was determined to be directed toward the nucleocapsid protein (NCp7), which contains two zinc fingers and plays vital roles in the viral life cycle. The "active sulfides" of this study cause the extrusion of zinc from these zinc fingers. Structure-activity relationships of the 2,2'-dithiobisbenzamides reveal that the disulfide bond and the ortho benzamide functional groups are essential for activity, with the best compounds having a carboxylic acid, carboxamide, or sulfonamide substituent. The 2-benzisothiazolones are formed from the disulfides both chemically and in vivo and their SAR mimics that of the 2,2'-dithiobisbenzamides. The antiviral activity of the disulfides may require cyclization to the isothiazolones. Two agents, PD 159206 and PD 161374, which showed good antiviral activity, physical properties, and excellent pharmacokinetics in mice, were selected for advanced studies.