Drug design and delivery最新文献

Syntheses of the two diastereomers (5a and 6a) of 5-(2,2-dichlorocyclopropyl)-, and of the four diastereomers (7a-10a) of 5-(2-chlorocyclopropyl)-2'-deoxyuridine are described. These, and corresponding diastereomers (5b and 6b; 7b-10b) of 5-(2,2-dibromocyclopropyl)- and 5-(2-bromocyclopropyl)-2'-deoxyuridine (prepared in an earlier investigation) were examined for antiviral and cytotoxic activity, in comparison with (E)-5-(2-bromovinyl)-2'-deoxyuridine (BVDU) and 5-fluoro-2'-deoxyuridine (FDU). 5-[(1R,2R)-2-Chlorocyclopropyl]-2'-deoxyuridine (9a) was the most active antiviral agent (IC50 = 25 micrograms/ml) against herpes simplex virus type 1 (HSV-1) relative to BVDU (IC50 = 0.082 microgram/ml). Compounds having the R configuration at the C-1 and/or C-2 positions of the 5-[2,2-dichloro(or 2-chloro)cyclopropyl] substituent exhibited the most potent antiviral activity. The cytotoxic activities of the 5-(2,2-dihalocyclopropyl)- (5-6a and b) and 5-(2-halocyclopropyl)- diastereomers (7-10a and b) were dependent upon both the configuration of the C-1 and/or C-2 cyclopropyl carbons and the nature of the halogeno (Cl, Br) substituent. 5-[(1R)-2,2-Dichlorocyclopropyl]-2'-deoxyuridine (6a) was the most active cytotoxic compound in the CCRF-CEM (IC50 = 17 microM) and HL-60 (IC50 = 64 microM) screens relative to FDU, which exhibited IC50 values of 4.7 x 10(-3) and 77 microM in these respective screens.

Five cellulose disintegrants--low-substituted hydroxypropylcellulose (L-HPC), microcrystalline cellulose (MCC), carboxymethylcellulose (CMC), cross-linked NaCMC (C.L.NaCMC), and CaCMC-were evaluated as directly compressed matrices for sustained-release (SR) tablets in vitro, using procainamide hydrochloride as a model drug. Coarser particles (14-19 microns) of the jet mill ground disintegrants, as well as intact disintegrants, provided rapidly disintegrating tablets with fast drug release but finer particles (2.5-3.5 microns) provided matrix-type SR tablets. The SR tablets based on non-ionic polymers (L-HPC and MCC) did not disintegrate at any pH; those based on anionic polymers (C.L.NaCMC and CaCMC) did not disintegrate at pH 1.2, but they disintegrated gradually from the exterior in water and in a pH 6.8 medium. We conclude that the particle size and concentration of the cellulose disintegrants are determinant factors in the formulation of SR matrices.

Three 22-(p-chloroaryl) analogues of cholesterol (6a-c) were synthesized and evaluated as potential inhibitors of the adrenal cholesterol side-chain cleavage enzyme, in comparison with the known 20-aryl analogue, 20-(p-chlorophenyl)-5-prenen-3 beta,20-diol (2b). All were potent inhibitors. An oxygen at C-22 (analogues 6a and 6b) enhanced the strong binding to the enzyme. Two compounds (6b and 6c) are potential substrates of the enzyme. Possible pharmaceutical uses for these compounds and their derivatives are discussed.

3-(3"Trifluoromethylphenoxy)-1,4-dihydropyridines containing phenoxycarbonyl, methoxycarbonyl or acetyl at the 1 position, and phenyl, n-butyl or methyl at the 4-position were synthesised (generalised structure 4). Four members of this series (4a-c, 4g)--the rest were not evaluated because of their facile oxidation to pyridines--were found to be inactive in maximal electroschock (MES) and subcutaneous pentylenetetrazole (scPTZ) screening tests in mice, suggesting that the 1-carbonyl-3-(3'-trifluoromethyl-phenoxyl)-1,4-dihydropyridyl++ + moiety is not a suitable anticonvulsant pharmacophore. 4-Phenyl-3-(3'-trifluoromethylphenoxy)pyridine (5a)--the oxidation product of 4a--was also inactive in both tests. In contrast, the isomeric 2-phenyl-3-(3'-trifluoromethylphenoxy)pyridine (7), whilst inactive in the scPTZ test, exhibited significant anticonvulsant activity in the mouse MES test (intraperitoneal administration; ED50 = 159 mg/kg), and increased activity following its oral administration in a rat MES test (ED50 = 31.9 mg/kg). It caused displacement of 10 microM [3H]flunitrazepam from mouse whole brain P2 pellets at 30 microM concentration, indicating low affinity for the benzodiazepine receptor(s).

Thirteen 5-[3-(1,4-dihydropyridyl)]-2H-tetrazol-2-acetic acids (18-30), seventeen esters (4-17, 32, 35, 41) and eight amides (31, 32-34, 36-40) were synthesized in order to investigate the effect of alpha-substituents (R1 = H, Me) and 1,4-dihydropyridyl substituents (R2 = aryl, alkyl; R3 = phenoxy, methoxy or amino) on anti-inflammatory activity. The effects of the R1, R2 or R3-substituents were variable but highly interdependent. The relative order of anti-inflammatory potency was generally acid greater than amide and ester. Methyl 2-methyl-2-(5-[3-(4-phenyl-1-carbamoyl-1,4-dihydropyridyl)]-2H- tetrazol-2-yl) acetate (35) was the most effective anti-inflammatory agent in the group, reducing inflammation 96% at 5 hr after a 50 mg/kg po dose, relative to ibuprofen's 52% inhibition at 5 hr after a 100 mg/kg po dose.

Systematic studies of the structure-activity relationships of atropine-like anticholinergic drugs have provided valuable information about the nature of the muscarinic receptor. In this study, the pharmacological activities of the (Z) and (E)-isomers of 2-phenylcyclohexyl diethylaminoethyl ether (1 and 2, respectively) in the isolated rat left atrium were investigated and compared with their activities in the isolated rat ileum preparation. Compound 1 was found to be one of the most ileal selective muscarinic antagonists reported to date. Other data concerning possible differences in the receptor-bound conformations of tropate- versus benzilate-derived muscarinic antagonists are also presented.

Reaction conditions for the covalent bonding of 5'-deoxy-5-fluorouridine to serum albumin microbeads by means of a water-soluble carbodiimide were studied. Optimum coupling of dFUR to the microbeads occurred when pure water was used as solvent. There was no significant difference in the bonding efficiency for microbeads prepared at different stirring speeds, and there was a limit to the amount of dFUR that could be bound with increasing reaction time. Yields were low possibly because of competing coupling reactions involving carbodiimide and other reactive groups in the protein. The release of dFUR from dFUR-bound microbeads was slow and biexponential. The fraction of dFUR bound in the interior of the microbeads increased with increasing reaction time.