Poly(butylene succinate)-based prepolymers containing itaconic acid units or maleic acid units in the main chain were synthesized through the condensation reaction of 1,4-butanediol, succinic acid, and itaconic acid or maleic acid. The resulting prepolymers, with weight-average molecular weights in the several thousands, were cured at 115°C with benzoyl peroxide to produce crosslinked polyesters that were insoluble in chloroform. Differential scanning calorimetry analysis revealed that the glass-transition temperature rose with crosslinking and that the melting temperature and heat of melting decreased with crosslinking. These results implied that crosslinking was successfully carried out and that the crystallinity of the polymer decreased. The crosslinked polymer showed lower biodegradability in the biochemical oxygen demand assay with activated sludge but retained some biodegradability.

Fluoroquinolone derivatives interact with methylxanthines (theophylline, caffeine) and metallic ion-containing drugs to different degrees. The rat appears to be a suitable model for predicting such interactions in man. It has been possible to determine the relationship between the chemical structure of the fluoroquinolone and the magnitude of the interaction. Fluoroquinolones with a bulky substituent at the position 8, such as sparfloxacin, lomefloxacin and fieroxacin, are less prone to interact with theophylline than those without an 8-substituent, such as enoxacin. This substituent determines the planarity of the whole fluoroquinolone molecule and the interaction tends to be more significant for planar fluoroquinolones. Furthermore, a 4'-nitrogen atom in the 7-piperazinyl group is essential for the interaction to occur. The nitrogen atom is possibly the site that binds cytochrome P-450, which catalyses theophylline metabolism. The reduction in bioavailability of fluoroquinolones by concurrent administration of aluminium hydroxide is more striking for derivatives with fewer substituents on the essential structure and on the piperazinyl group, such as norfloxacin, ciprofloxacin and enoxacin. Substitution at the 5-position diminishes the interaction, which suggests that the 5-substituent may affect the formation and/or stability of unabsorbable chelate complex which is the probable cause of the interaction. These findings are potentially useful in designing fluoroquinolones less prone to drug interactions.

Aldose reductase (AR) is an NADPH-dependent enzyme implicated in diabetic complications. AS-3201 [(R)-(-)-2-(4-bromo-2-fluorobenzyl)-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine-4-spiro-3'-pyrrolidine-1,2',3,5'-tetrone] is a structurally novel and potent ARI with an inhibitor constant (K(i) = 10(-)(10) M) 2000-fold lower than that of its optical antipode (S-isomer). To elucidate the inhibition modes and the stereochemical differences in their inhibitory potencies, we examined the interaction of these R- and S-isomers with AR under physiological conditions. Enzyme kinetic analysis, which was performed by using physiological substrates at 37 degrees C, showed that both isomers selectively act on the E-NADP(+) complex in both the forward and reverse reactions of AR. However, fluorometric titration analysis demonstrated that the affinities of the isomers for the E-NADP(+) complex are about the same as those for the E-NADPH complex and the apoenzyme. These results suggested that the selective binding to the E-NADP(+) complex arises from the predominance of this enzyme form during steady-state turnover rather than from binding specificity. Both the competition with a known active site-directed ARI and the protective effect on AR inactivation by N-bromosuccinimide showed that the isomers bind to the active site of the enzyme, but the thermodynamic parameters for the binding to AR indicated that additional hydrogen bonds and/or van der Waals interactions contribute to the energetic stabilization in the E-R-isomer complex. Molecular modeling, together with the deductions from spectroscopic studies, suggested that the succinimide ring and the 4-bromo-2-fluorobenzyl group of the R-isomer are optimally located for formation of a hydrogen-bonding network with AR, and that the latter benzyl group is also effective for the differentiation between AR and aldehyde reductase (a closely related enzyme).

A structurally original series of N-(1-ethyl-4-methylhexahydro-1,4-diazepin-6-yl)pyridine-3-carboxamides derived from the corresponding benzamide 5 were prepared and evaluated for their binding affinity for the dopamine D(2) and serotonin 5-HT(3) receptors using rat striatum and rat cortical membrane, respectively. Many of the synthesized pyridine-3-carboxamides exhibited nanomolar binding affinity for the serotonin 5-HT(3) receptor along with moderate to high binding affinity for the dopamine D(2) receptor. Introduction of the more lipophilic bromine atom and methylamino group at the 5- and 6-positions of the pyridine ring, respectively, enhanced the affinity for the dopamine D(2) receptor while keeping a potent serotonin 5-HT(3) receptor binding affinity. As a result of structure-affinity relationships, the 5-bromo-2-methoxy-6-methylaminopyridine-3-carboxamide 53 was selected as the most promising product showing a high binding affinity for both receptors. Compound 53 affinity for the dopamine D(2) and serotonin 5-HT(3) receptors was much more potent than that of metoclopramide (dopamine D(2) receptor; 23.3 nM vs 444 nM, serotonin 5-HT(3) receptor; 0.97 nM vs 228 nM). Optical resolution of the racemate 53 brought about a dramatic change in the pharmacological profile with (R)-53 exhibiting a strong affinity for both the dopamine D(2) and serotonin 5-HT(3) receptors, while the corresponding (S)-53 had a potent serotonin 5-HT(3) receptor binding affinity and a moderate dopamine D(2) receptor binding affinity. X-ray crystallographic study of (R)-53 revealed the existence of two energically stable conformers just like two mirror images. This may account for (R)-53 high affinity for both the dopamine D(2) and serotonin 5-HT(3) receptors. Pharmacologically, (R)-53 [AS-8112] showed a potent antagonistic activity for both the dopamine D(2) and serotonin 5-HT(3) receptors in vivo tests and dose-dependently inhibited both the incidence and frequency of emetic episodes induced by cisplatin (ferrets) and morphine (dogs) with ID(50) values of 27.1 microg/kg, po and 136 microg/kg, po, respectively. On the basis of this pharmacological profile, (R)-53 is now under further investigation as a potential broad antiemetic agent.

Comparative molecular field analysis (CoMFA) has been used in drug design and three-dimensional quantitative structure-activity relationships (3D-QSAR). In CoMFA analysis, Partial Least-Squares (PLS) is used to correlate a large number of variables with biological activity. However, PLS may not clearly indicate which variables affect the biological activity of compounds. We have developed PWPLS (Prediction-Weighted Partial Least-Squares) that can select good predictor variables and weight each predictor variable to improve the predictiveness of its model. In addition to PWPLS, we developed another method, Q 2 oriented variable selection (QOVS), to select variables that also affect predictiveness of its model. In this paper, we applied PWPLS and QOVS to the CoMFA study reported by Dunne et al. for binding 21 steroids to corticosteroid-binding globulin (CBG).