Quantitative structure-activity relationships. 3.1 A comparison of different Free-Wilson models

The Fujita-Ban model and the classical Free-Wilson model are shown to be linearly related: the de novo group contributions obtained by one model are linear transformations of those obtained by the other model. An example is given to illustrate this linear dependence. The Fujita-Ban model is characterized by a number of advantages as compared with the classical Free-Wilson model: no transformation of the structural matrix and no symmetry equations are necessary; all group contributions are based on an arbitrarily chosen reference compound, preferably the unsubstituted compound; the constant term, which is the theoretically predicted activity value of the reference compound, and the values of the group contributions are not markedly influenced by addition or elimination of a compound; the problem of linear dependence (the singularity problem) sometimes can be circumvented by preparation of a contracted matrix; if the unsubstituted compound is chosen as reference compound, the group contributions are numerically equivalent to Hansch-derived group contributions; therefore, the Hansch approach and the Fujita-Ban model can be combined to a mixed approach. Taking all these facts into consideration, the Frujita-Ban model is recommended as the most suitable approach for the calculation of de novo group contributions.     

Quantitative structure-activity relationships of 2, 4-diamino-5-(2-X-benzyl)pyrimidines versus bacterial and avian dihydrofolate reductase

Quantitative structure-activity relationships (QSAR) have been formulated for a set of 15 2,4-diamino-5-(2-X-benzyl)pyrimidines versus dihydrofolate reductase from Lactobacillus casei and chicken liver. QSARs were also developed for comprehensive data sets containing mono-, di-, and trisubstituted benzyl derivatives. Particular emphasis was placed on the role played by ortho substituents in the overall binding process and subsequent inhibition of the catalytic process in both the prokaryotic and eucaryotic DHFRs. Comparisons between the two QSARs reveal subtle differences at specific positions which can be optimized to design more selective antibacterial agents.     

Synthesis and structure-activity relationships of carboxylated chalcones: a novel series of CysLT1 (LTD4) receptor antagonists

The synthesis and CysLT1 antagonistic activities of a new series of 2-, 3-, and 4-(2-quinolinylmethoxy)- and 3- and 4-[2-(2-quinolinyl)ethenyl]-substituted, 2'-, 3'-, 4'-, or 5'-carboxylated chalcones are described. Structure-activity relationship studies indicate a preference for the presence of a negatively charged (acidic) moiety, although in some cases nitrile or ester analogues also exhibit moderate activity. The quinoline moiety may be substituted at either the 3- or the 4-position. Replacement of this heterocycle by other aromatic groups results in compounds with comparable affinities [2-(7-chloroquinoline), 1-(1-methyl-2-benzimidazole), or 1-(2-benzothiazole)] or substantially lower activities [1-(1-ethoxyethyl)-2-benzimidazole, 2-naphthyl, or phenyl]. The quinoline and chalcone moieties may be connected by either an ethenyl or a methoxy spacer. The acidic moiety at the chalcone B ring may be attached to the 2'-, 3'-, 4'-, or 5'-position, for both the 3- and 4-substituted chalcones. There are no general patterns to specify which substitution positions gave the most potent compounds. The series contains several potent CysLT1 receptor antagonists, with K(D) values approaching the nanomolar range, as measured by the displacement of [3H]LTD4 from guinea pig lung membranes. Antagonism of LTD4-induced contraction of guinea pig ileum, the inhibition of antigen-induced contraction of guinea pig trachea in vitro, and the inhibition of LTD4-induced increase of vascular permeability in vivo are determined for chalcones with high CysLT1 receptor affinities (K(D) values below 0.1 microM). 2'-Hydroxy-4-(2-quinolinylmethoxy)-5'-(5-tetrazolyl)chalcone (14, VUF 4819) showed good activity in both in vitro and in vivo assays and has been selected for further evaluation.     

Prooxidant character of flavonoid cytotoxicity: structure-activity relationships

Although differences in visual pigments between developmental stages of the European eel are well known, the expected differences in spectral sensitivity have not been demonstrated at the electrophysiological level. In fact, one past electroretinographic study led to the conclusion that in eels there is no change in scotopic sensitivity, with increasing sexual maturity. In the present experiments, electroretinograms (ERGs) were recorded from in situ eyecups of immobilized eels Anguilla anguilla (L.) caught in coastal running waters. It was shown that the ERG b-wave is as good an indicator of spectral sensitivity as the unmasked late receptor potential (LRP) which directly reflects the responsiveness of photoreceptors. Complete spectral-sensitivity curves, based on b-wave thresholds and on thresholds of LRP subsequently isolated by means of sodium iodate, have been obtained in the same eel. Using fitted amplitude-log intensity functions for threshold calculation, and two models for computer-assisted fitting of spectral-sensitivity curves, significant differences in lambda max were found between yellow and silver developmental stages of the eel, identified by ocular index measurements.     

Taxol: the chemistry and structure-activity relationships of a novel anticancer agent

Taxol is an exciting new anticancer drug, showing clinical activity against ovarian and breast cancer. Its development as a clinically useful drug has involved major efforts to overcome the supply problem; this has now been done, and the focus of interest has moved to the development of improved analogs of the drug. Recent notable achievements include the first total synthesis of taxol, and the first indications of its binding site on tubulin.     

Substituted (S)-phenylpiperidines and rigid congeners as preferential dopamine autoreceptor antagonists: synthesis and structure-activity relationships

A series of (S)-phenylpiperidines in which the substituents on the aromatic ring and nitrogen have been varied has been prepared. They have been evaluated pharmacologically to explore the importance of these substituents for the interaction with central dopamine (DA) receptors. On the basis of biochemical and behavioral data in rats, several of these compounds are characterized as centrally acting DA autoreceptor antagonists. (S)-Phenylpiperidines having an aromatic substituent with a high group dipole moment in the 3-position, i.e., meta with respect to the piperidine ring, and being N-substituted with a propyl group were found to be highly active in vivo on the synthesis and turnover of dopamine. However, they do not induce strong hypoactivity or catalepsy. Interestingly, the most active compounds in vivo were found to display only low affinity for DA D2 and D3 receptors in vitro. In addition, 7-triflate-substituted octahydrobenzo[f]quinolines and 6-triflate-substituted hexahydro-1H-benz[e]indoles have been prepared and pharmacologically evaluated. The trans isomers of these rigid structures were found to display a pharmacological profile similar to that of the flexible phenylpiperidines. The corresponding cis isomers were found to be inactive in vivo.     

Synthesis and structure-activity relationships of 7-(2-aminoalkyl)morpholinoquinolones as anti-Helicobacter pylori agents

A series of the titled compounds was synthesized and tested for anti-Helicobacter pylori activities. We discovered Y-34867 having the most potent activity against Helicobacter pylori among the quinolones tested along with high photostability. Furthermore, Y-34867 showed an excellent therapeutic effect in the experimental Helicobacter pylori infected Mongolian gerbil model.     

Acetylcholinesterase inhibitors: synthesis and structure-activity relationships of omega-[N-methyl-N-(3-alkylcarbamoyloxyphenyl)- methyl]aminoalkoxyheteroaryl derivatives

Acetylcholinesterase (AChE) inhibitors are one of the most actively investigated classes of compounds in the search for an effective treatment of Alzheimer's disease. This work describes the synthesis, AChE inhibitory activity, and structure-activity relationships of some compounds related to a recently discovered series of AChE inhibitors: the omega-[N-methyl-N-(3-alkylcarbamoyloxyphenyl)methyl]aminoalkoxy xanthen-9-ones. The influence of structural variations on the inhibitory potency was carefully investigated by modifying different parts of the parent molecule, and a theoretical model of the binding of one representative compound to the enzyme was developed. The biological properties of the series were investigated in some detail by considering not only the activity on isolated enzyme but the selectivity with respect to butyrylcholinesterase (BuChE) and the in vitro inhibitory activity on rat cerebral cortex as well. Some of the newly synthesized derivatives, when tested on isolated and/or AChE-enriched rat brain cortex fraction, displayed a selective inhibitory activity and were more active than physostigmine. In particular, compound 13, an azaxanthone derivative, displayed the best rat cortex AChE inhibition (190-fold higher than physostigmine), as well as a high degree of enzyme selectivity (over 60-fold more selective for AChE than for BuChE). When tested in the isolated enzyme, compound 13 was less active, suggesting some differences either in drug availability/biotransformation or in the inhibitor-sensitive residues of the enzyme when biologically positioned in rat brain membranes.     

Inhibitors of acyl-CoA:cholesterol O-acyltransferase. 2. Identification and structure-activity relationships of a novel series of N-alkyl-N-(heteroaryl-substituted benzyl)-N'-arylureas

A series of N-alkyl-N-(heteroaryl-substituted benzyl)-N'-arylurea and related derivatives represented by 2 and 3 have been prepared and evaluated for their ability to inhibit acyl-CoA:cholesterol O-acyltransferase in vitro and to lower plasma cholesterol levels in cholesterol-fed rats in vivo. Among these novel compounds, the type 3 series was superior. A pyrazol-3-yl group on the N-benzyl group of this trisubstituted urea (i.e. 3, Ar1 = pyrazol-3-yl) was identified as a heteroaromatic ring providing a good profile of biological activity. As a result of optimization of the combination with the N-alkyl group (R) and N-aryl group (Ar3), compound 3aq (FR186054) was identified as a new, orally efficacious ACAT inhibitor, which exhibited potent in vitro ACAT inhibitory activity (rabbit intestinal microsomes IC50 = 99 nM) and excellent hypocholesterolemic effects in cholesterol-fed rats, irrespective of administration mode (ED50 = 0.046 mg/kg dosed via the diet, ED50 = 0. 44 mg/kg administered by gavage in PEG400 vehicle). Moreover, a toxicological study revealed compound 3aq to be nontoxic to the adrenal glands of dogs when tested at a single dose of 10 mg/kg po.     

The discovery and structure-activity relationships of nonpeptide, low molecular weight antagonists selective for the endothelin ET(B) receptor

The systematic modification of the ETA selective N-(5-isoxazolyl)benzene-sulfonamide endothelin antagonists to give ETB selective antagonists is reported. The reversal in selectivity was brought about by substitution of the 4-position with aryl and substituted aryl groups. Of all the aromatic substituents studied, the para-tolyl group gave rise to the most active and selective ETB antagonist. Larger substituents caused a decrease in both ETB activity and selectivity. A similar trend was observed by substitution at the 5-position of the N-(5-isoxazolyl)-2-thiophenesulfonamide ETA receptor antagonists. The para-tolyl group was again found to be optimal for the ETB activity and selectivity. The structural features that were found to be favorable for binding to the ETB receptor, that is, the presence of a linear, conjugated pi-system of definite shape and size, have been successfully incorporated into the design of ETB selective polycyclic aromatic sulfonamides antagonists.     

2-Azetidinone cholesterol absorption inhibitors: structure-activity relationships on the heterocyclic nucleus

A series of azetidinone cholesterol absorption inhibitors related to SCH 48461 ((-)-6) has been prepared, and compounds were evaluated for their ability to inhibit hepatic cholesteryl ester formation in a cholesterol-fed hamster model. Although originally designed as acyl CoA: cholesterol acyltransferase (ACAT) inhibitors, comparison of in vivo potency with in vitro activity in a microsomal ACAT assay indicates no correlation between activity in these two models. The molecular mechanism by which these compounds inhibit cholesterol absorption is unknown. Despite this limitation, examination of the in vivo activity of a range of compounds has revealed clear structure-activity relationships consistent with a well-defined molecular target. The details of these structure-activity relationships and their implications on the nature of the putative pharmacophore are discussed.     

Synthesis and structure-activity relationships of 2-pyridones: II. 8-(Fluoro-substituted pyrrolidinyl)-2-pyridones as antibacterial agents

The 8-position side chain of 2-pyridones is believed to be involved in the binding with bacterial DNA gyrase to form the ternary complex, making them very important for the activity of 2-pyridones. A series of 2-pyridones having fluoro-substituted amines at the 8-position has been synthesized and their antibacterial activities and parmacokinetic properties are reported.     

The structure-activity relationships of a series of suicide inhibitors of phospholipase A2

A series of mechanism-based inhibitors of phospholipase A2 (SIBLINKS) were synthesized. These new SIBLINKS are phospholipid analogues that contain a para-substituted phenyl 3,3-dimethylglutaryl group in the place of the sn-2 acyl chain. The effect of the phenyl leaving group on inhibitory activity was studied by varying the electron-withdrawing ability of the para-substituted group. A strong correlation was observed between the leaving group potential of the suicide inhibitor and the inhibitory activity of the derivative toward cobra venom phospholipase A2.     

Endothelin receptor antagonists: synthesis and structure-activity relationships of substituted benzothiazine-1,1-dioxides

The development of benzothiazine-1,1-dioxide derivatives as a new structural class of potent endothelin receptor antagonists is described. Structure-activity relationships (SAR) revealed that PD164800 (1) is a potent antagonist of the ETA receptor subtype.     

Induction of lymphoproliferative popliteal lymph node reaction by hydantoin derivatives: structure-activity relationships

We evaluated the ability of a series of 3-phenylhydantoin derivatives to induce a lymphoproliferative popliteal lymph node reaction in C57B1/6 mice. 5-Aryl-3-phenylhydantoins induced a significant lymphoproliferative reaction, whereas the 5-alkyl-substituted and the unsubstituted 3-phenylhydantoins did not. 5-Alkyl-3-phenylhydantoins were unable to induce a lymphoproliferative reaction, unlike the corresponding 5-alkyl-3-phenyl-2-thiohydantoins, which have been reported to induce a significant lymphoproliferative reaction in the same strain of mice. Based on these results, we suggest that, to induce a lymphoproliferative popliteal lymph node reaction, hydantoins have to bind covalently to proteins through the N-atoms if they are activated by electrophilic groups bound to the hydantoin ring. We also suggest that 2-thiohydantoins can bind through their S-atom, whereas hydantoins cannot do so through their O-atoms.