1-(2-pyridinyl)piperazine derivatives with antianaphylactic, antibronchospastic, and mast cell stabilizing activities

New 1-(2-pyridinyl)piperazine derivatives were synthesized and tested as inhibitors of the reaginic passive cutaneous anaphylaxis in the rat (PCA), of the histamine-induced bronchospasm in the guinea pig, and of the rat mesenteric mast cell degranulation induced by compound 48/80. On the basis of test results, a series of N-(substituted phenyl)-omega-[4-(2-pyridinyl)-1-piperazinyl]alkanamides was prepared. The nature of substituents at the anilide ring strongly influenced mast cell stabilizing activity, whereas it was less determining in the case of the other two tests. No clear correlation between the most common physicochemical parameters (pi, sigma, Vw volume) of substituents and activity could be detected. With regard to the position of substituents at the anilide ring, the rank order of potency, in the PCA and bronchoconstriction tests, was para greater than meta greater than ortho. Introduction of substituents in the 1-(2-pyridinyl)piperazinyl moiety of the N-(substituted phenyl)propanamide derivatives hardly affected activity, or the effect was deleterious. Some of the new compounds exhibited a simultaneous remarkable activity in all the three assays employed.     

QSAR of matrix metalloproteinase inhibitor N-[(substituted phenyl)sulfonyl]-N-4-nitrobenzylglycine hydroxamates using LFER model.

QSAR analyses of matrix metalloproteinase (MMP) inhibitor N-[(substituted phenyl)sulfonyl]-N-4-nitrobenzylglycine hydroxamates, recently reported by Scozzafava and Supuran, have been attempted using linear free energy related (LFER) model of Hansch to explore the contribution patterns of the phenyl ring substitutions (P1' anchoring site of the ligands) to the activities against MMP-1, -2, -8 and -9 (pC1, pC2, pC, and pC9) and C. histolyticum collagenase (pC(ChC)) and also to find out relations among the activities. Multiple regression analyses applied on the data set reveal that electron withdrawing meta substituents and lipophilic ortho and meta substituents are conducive to pC1 while presence of substituents (larger than hydrogen) at vicinal positions on the phenyl ring and bulkier ortho substituents are detrimental to the activity. Again, the electronic and steric parameters of meta substituents (sigmam and MRm) and lipophilicity parameter of ortho substituents (pio) contribute significantly to pC2, pC8 and pC9: sigmam shows parabolic relationships (optimum sigmam values being 0.518, 0.584 and 0.522 respectively) and steric bulk of meta substituents has negative impact while presence of hydrophilic groups at the ortho positions increases the activities. Further, presence of electron withdrawing meta substituents and hydrophilic para substituents is conducive to the C. histolyticum collagenase (pC(ChC)) activity. The study suggests that the structural and physicochemical requirements of the P1' anchoring site for the activities against MMP-2, -8 and -9 are highly intercorrelated and these are comparatively less correlated with those for the activities against MMP-1 and C. histolyticum collagenase.     

Quantitative structure-activity relationships of inhibitors of immune complex-induced inflammation: 1-phenyl-3-aminopyrazoline derivatives

Quantitative structure-activity relationships (QSAR) of the 1-phenyl-3-aminopyrazoline analogues as inhibitors of immune complex-induced inflammation have been studied. The correlation suggests that the overall size of the phenyl substituents are of importance, and bulky groups have negative effects on potency. The negative steric effects are gradually increased from ortho to meta to para positions. The negative steric effects were sometimes altered by the electronic effects of the substituents. Electron-releasing groups on the phenyl ring increased potency, while electron-withdrawing groups decreased it. Ortho substituents, however, have unaccounted for additional deleterious effects described here with an indicator variable. The octanol-water partition coefficient (log P) and dissociation constants (pKa) of the 1-(m-trifluoromethylphenyl)-3-aminopyrazoline analogue have been experimentally determined.     

Relationships between the lipophilicity of some 1,4-piperazine derivatives of aryloxyaminopropanols and their beta-andrenolytic activity

Nineteen 1,4-piperazine derivatives of aryloxyaminopropanol were evaluated with respect to beta-adrenolytic activity. The retention factors obtained from HPLC, RM values obtained from partition TLC and the lipophilic Hansch's (4) constants pi were determined and the compounds were studied with respect to their lipophilicity based on chromatographic properties. The study of the influence of different substituents introduced at the para position on the phenyl ring on the retention factor indicated the log k vs. the number of carbon atoms in R1 substituent to be a linear relationship. Attempts have been made to relate the beta-adrenolytic activity to the lipohydrophilic parameters by deriving a quantitative relationship between them. Significant parabolic correlation was observed between the beta-adrenolytic activity and the logarithm of the retention factor, log k. An analogous relationship was obtained between the beta-adrenolytic activity of the compounds and the RM values obtained from partition TLC as well as Hansch's lipophilic constants pi.     

Quantitative structure-activity relationship of 5-(X-benzyl)-2,4-diaminopyrimidines inhibiting bovine liver dihydrofolate reductase.

The inhibitory effect for a set of 23 5-(X-benzyl)-2,4-diaminopyrimidines acting on bovine liver dihydrofolate reductase (DHFR) had led to the following quantitative structure-activity relationship (QSAR): log 1/C = 0.62pi3 + 0.33epsilon sigma + 4.99, where r = 0.931 and s = 0.146. C in this expression is the molar concentration of inhibitor producing 50% inhibition, pi3 is the hydrophobic parameter for substituents on the 3 position of the phenyl moiety, and epsilon sigma is the the sum of the Hammett sigma constants for the 3, 4, and 5 substituents of the phenyl ring.     

QSAR with electrotopological state atom index: human factor Xa inhibitor N2-aroylanthranilamides

Recently, N2-aroylanthranilamides have been reported as novel series of possible anticoagulant drug candidates and the two aryl rings (A and B) have been suggested to interact with S1 and S4 regions, respectively, of human factor Xa (hfXa). In the present effort, quantitative structure-activity relationship (QSAR) of the hfXa binding affinity of 32 N2-aroylanthranilamides have been attempted, in continuation of our previous report on the QSAR analysis of the data set using linear free energy related (LFER) model, with electrotopological state atom (ETSA) index (Kier and Hall, 1991, Adv. Drug Design., 22, 1-38), to explore the atoms/regions of the compounds that modulate the activity comparatively to the greater extent. The univariate and bivariate relations involving the ETSA values of different common atoms of the compounds show importance of the atom nos. 12, 3 and 17 (arbitrary numbering): B ring carbon bearing meta R2 substituents, C ring carbon bearing R4 substituent, and carbonyl oxygen of A ring amide linkage. The importance of atom 12 is suggested to be due to detrimental effects of meta R2 substituents (B ring) on the hfXa binding affinity, which may be owing to interference in the attainment of the proper orientation of the phenyl ring in the S4 site. Atom 3 signifies the impact of R4 substituents (central C ring) on the binding affinity. Again, atom 17 (carbonyl oxygen of A ring amide linkage) has been suggested to form hydrogen bonding with the NH group of the other amide linkage, producing a pseudo ring and thus stabilizing the structure. The relations were improved further using indicator and physicochemical variables and the present results are in good agreement with the previous findings of the Hansch analysis.     

Actinidin hydrolysis of substituted-phenyl hippurates: a quantitative structure-activity relationship and graphics comparison with hydrolysis by papain

The hydrolysis of 29 phenyl hippurates (XPhOCOCH2NHC(=O)C6H5) by the cysteine protease actinidin has been studied and a quantitative structure-activity relationship (QSAR) has been formulated: log 1/Km = 0.74 sigma + 0.50 pi'3 + 0.24MR4 + 2.90. In this expression Km is the Michaelis constant, sigma is the Hammett constant, pi'3 is the hydrophobic parameter for the more hydrophobic of the two meta substituents, and MR4 is the molar refractivity of para substituents. The QSAR for actinidin is compared with a similar one obtained for another cysteine plant protease papain. A color stereo computer graphics model constructed from the X-ray crystallographic coordinates of actinidin is compared with those of our previously reported models for papain.     

Topical carbonic anhydrase inhibitors. III: Optimization model for corneal penetration of ethoxzolamide analogues

An analogue series representing modification to the benzene ring of ethoxzolamide has been evaluated for solubility, pKa, partitioning, and permeability across excised rabbit corneas. These physical parameters were correlated to Hammett sigma (para) and/or Hansch pi parameter values for each compound. From these correlations, a mathematical model was developed relating corneal permeability to molecular modifications of ethoxzolamide. A three-dimensional plot of maximum attainable penetration rate versus sigma (para) and pi yielded an optimal range of pi and sigma values from which an optimally penetrating analogue could be designed.     

3-(4-phenoxyphenyl)pyrazoles: a novel class of sodium channel blockers

A series of 3-(4-phenoxyphenyl)-1H-pyrazoles were synthesized and characterized as potent state-dependent sodium channel blockers. A limited SAR study was carried out to delineate the chemical requirements for potency. The results indicate that the distal phenyl group is critical for activity but will tolerate lipophilic (+pi) electronegative (+sigma) substituents at the ortho and/or para position. Substitution at the pyrazole nitrogen with a H-bond donor improves potency. Compound 18 showed robust activity in the rat Chung neuropathy paradigm.     

Thiopurine methyltransferase: structure-activity relationships for benzoic acid inhibitors and thiophenol substrates

Twenty-seven substituted benzoic acids have been studied as inhibitors of partially purified human renal thiopurine methyltransferase (TPMT). Quantitative structure-activity relationship (QSAR) analysis resulted in the following equation: pI50 = 1.25( +/- 0.53)pi'3 + 0.73( +/- 0.38)MR3,4 + 2.92( +/- 0.39). In this equation pI50 is the -log of the concentration of compound that inhibits the enzyme activity by 50% (IC50);pi'3 is the relative hydrophobicity of the more hydrophobic of the two meta substituents; and MR3,4 is the molar refractivity of the more hydrophobic of the two meta substituents and of the para substituent on the phenyl ring. In addition, 14 substituted thiophenols were tested as substrates for the enzyme. All 14 thiophenols tested were excellent substrates with Km constants (0.8-7.8 microM) that were at least 2 orders of magnitude lower than those of any known thiopurine substrate for TPMT. However, there was no discernible relationship between the activities of thiophenol substrates and their physicochemical parameters. These results suggest that benzoic acid inhibitors of and thiophenol substrates for TPMT may interact with different sites on the enzyme.     

Cyclohex-1-ene carboxylic acids: synthesis and biological evaluation of novel inhibitors of human 5 alpha reductase

In search of novel nonsteroidal mimics of steroidal inhibitors of 5 alpha reductase, 4-(2-phenylethyl)cyclohex-1-ene carboxylic acids 1-5 were synthesized with different substituents in para position of the phenyl ring (1: N, N-diisopropylcarbamoyl, 2: phenyl, 3: phenoxy, 4: benzoyl, and 5: benzyl). The principal synthetic approach for the desired compounds consisted of a Wittig olefination between 1, 4-dioxaspiro [4.5]-decane-8-carbaldehyde (4g and the appropriate phosphonium salts. The compounds were tested for inhibition of human 5 alpha reductase isozymes 1 and 2 using DU 145 cells and preparations from prostatic tissue, respectively. They turned out to be good inhibitors of the prostatic isozyme 2 with compound 1 being the most potent one (IC(50) = 760 nM). Isozyme 1 was only slightly inhibited. It is concluded that the novel structures are appropriate for being further optimized, aiming at the development of a novel drug for the treatment of benign prostatic hyperplasia.     

Structure-activity relationship of the ficin hydrolysis of phenyl hippurates. Comparison with papain, actinidin, and bromelain

A study of the hydrolysis of 30 substituted-phenyl hippurates by the enzyme ficin has been made. From the results the following quantitative structure--activity relationship (QSAR) has been derived: log 1/Km = 0.79 pi'3 + 0.58 sigma + 0.28 MR4,5 + 3.70. In this expression Km is the Michaelis constant, pi'3 refers to the more hydrophobic of the two meta substituents, and MR4,5 is the molar refractivity of substituents in the 4- and 5-positions of the phenyl ring. This QSAR is compared with those from papain, actinidin, bromelain B, and bromelain D.     

Muscarinic receptor binding profile of para-substituted caramiphen analogues

Para-substituted analogues of the antimuscarinic agent caramiphen were synthesized and evaluated for their ability to bind to the M1 and M2 subtypes of the muscarinic receptor. The purpose of the set was to look for a possible relationship in binding affinity or receptor subtype selectivity with aromatic substituent parameters such as Hammett's sigma or Hansch's pi values. It is felt this could be determined initially with only four properly chosen substituents. In this approach, substituents were chosen which have an extreme value for sigma and for pi, in a positive and negative direction, in all combinations. The substituents chosen for examination were amino (-sigma, -pi); 1-pyrrolidinyl (-sigma, +pi); 1-tetrazolyl (+sigma, -pi), and iodo (+sigma, +pi). It was determined in this research that caramiphen binds with high affinity (Ki = 1.2 nM) and is selective for the M1 over M2 muscarinic receptor subtype (26-fold). An examination of para-substitution reveals that compounds with electron-withdrawing (+sigma) substituents showed M1 selectivity, while the derivatives with electron-donating groups (-sigma) were nonselective in the binding assays. On the basis of this finding, the nitro and cyano derivatives were prepared and found to be M1 selective. The + sigma derivatives showed a decrease in M2 affinity while the p-nitro and p-iodo derivatives retained approximately equal affinity as caramiphen for the M1 site. The nitro- and iodocaramiphen derivatives were as potent (M1, Ki = 5.52 and 2.11 nM, respectively) and showed a greater selectivity of M1 over M2 binding than the M1 prototypical agent pirenzepine (M1, Ki = 5.21 nM).     

Cyclohexylcarbamic acid 3'- or 4'-substituted biphenyl-3-yl esters as fatty acid amide hydrolase inhibitors: synthesis, quantitative structure-activity relationships, and molecular modeling studies

Fatty acid amide hydrolase (FAAH) is a promising target for modulating endocannabinoid and fatty acid ethanolamide signaling, which may have important therapeutic potential. We recently described a new class of O-arylcarbamate inhibitors of FAAH, including the cyclohexylcarbamic acid biphenyl-3-yl ester URB524 (half-maximal inhibitory concentration, IC(50) = 63 nM), which have significant anxiolytic-like properties in rats. In the present study, by introducing a selected group of substituents at the meta and para positions of the distal phenyl ring of URB524, we have characterized structure-activity profiles for this series of compounds and shown that introduction of small polar groups in the meta position greatly improves inhibitory potency. Most potent in the series was the m-carbamoyl derivative URB597 (4i, IC(50) = 4.6 nM). Furthermore, quantitative structure-activity relationship (QSAR) analysis of an extended set of meta-substituted derivatives revealed a negative correlation between potency and lipophilicity and suggested that small-sized substituents may undertake polar interactions with the binding pocket of the enzyme. Docking studies and molecular dynamics simulations, using the crystal structure of FAAH, indicated that the O-biphenyl scaffold of the carbamate inhibitors can be accommodated within a lipophilic region of the substrate-binding site, where their folded shape mimics the initial 10-12 carbon atoms of the arachidonyl moiety of anandamide (a natural FAAH substrate) and methyl arachidonyl fluorophosphonate (a nonselective FAAH inhibitor). Moreover, substituents at the meta position of the distal phenyl ring can form hydrogen bonds with atoms located on the polar section of a narrow channel pointing toward the membrane-associated side of the enzyme. The structure-activity characterization reported here should help optimize the pharmacodynamic and pharmacokinetic properties of this class of compounds.     

Inhibition of prostaglandin 15-hydroxydehydrogenase by sulphasalazine and a novel series of potent analogues

The ability of sulphasalazine, its colonic metabolites and various analogues to inhibit prostaglandin inactivation by two purified preparations of type INAD+-dependent prostaglandin 15-hydroxydehydrogenase or in various 100,000 g cytosolic supernatants was investigated using PGF2 alpha as substrate and radio-TLC. Bovine lung and human placental PGDH were inhibited in a dose-dependent and apparently non-competitive manner by sulphasalazine and most of the 26 salazine/sulphasalazine analogues tested, but the potencies of the analogues varied considerably. In a survey of structure-activity effects testing 30 drugs at a fixed dose (50 microM) in six test systems, it was established that only two aromatic rings are needed and that optimal PGDH inhibition requires -CH2COOH and -OH at positions 1 and 2 in the salicyl C ring system. Homosalazine was thus established as the type compound of a novel series of powerful PGDH inhibitors. Electronegative substituents meta or para in ring B produce compounds with greater than 150 X inhibitory potency of sulphasalazine, and a significant linear correlation (r = 0.82, P less than 0.002) was found between the inhibitory activity and the Hammett sigma substituent constant in this series of ten homosalazine analogues.     

A quantitative structure-activity relationship and molecular graphics study of carbonic anhydrase inhibitors

A quantitative structure-activity relationship (QSAR) (log K = 1.55 alpha + 0.64 log P - 2.07I1 - 3.28I2 + 6.94) has been formulated for the binding of a set of substituted benzenesulfonamides to human carbonic anhydrase. The binding constant (K) are from the studies of King and Burgen [Proc. R. Soc. Lond. B. 193:107-125 (1976)], sigma is the Hammett electronic substituent constant, P is the octanol/water partition coefficient, and I1 and I2 are indicator variables for meta and ortho substituents, respectively. The negative coefficients with the indicator variables suggest steric hindrance by these substituents in contrast to para substituents. Qualitative features of the QSAR are correlated with a color stereomolecular graphics model of the enzyme-inhibitor complex which was constructed from the X-ray crystallographic coordinates of the enzyme.     

Synthesis and in vitro pharmacology of arpromidine and related phenyl(pyridylalkyl)guanidines, a potential new class of positive inotropic drugs

Replacement of the cimetidine moiety in impromidine (1,N1-[3-(1H-imidazol-4-yl)propyl]-N2-[2-[[(5-methyl-1H-imidazol-4- yl)methyl]thio]ethyl]guanidine) by more lipophilic H2-nonspecific pheniramine-like structures resulted in potent H2 agonists with up to 160 times the activity of histamine in the isolated, spontaneously beating guinea pig right atrium. Additionally, the compounds proved to be moderate H1 antagonists. Highest H2-agonistic potency was found in compounds characterized by a three-membered carbon chain connecting the aromatic rings and the guanidine group. The activity in the atrium was increased 2-4-fold by halogen substituents in the meta or para position of the phenyl ring. Highest H1-antagonistic potency resides in the group of para-halogenated compounds, p-F representing the optimal substituent in both receptor models. The corresponding guanidine 52 (arpromidine, N1-[3-(4-fluorophenyl)-3-pyridin-2-ylpropyl]-N2-[3-(1H-imidazol-4- yl)propyl]guanidine) combines about 100 times the activity of histamine at the H2 receptor with H1-antagonistic potency in the range of pheniramine. Further increase in the activity on the atrium was achieved by disubstitution with halogen on the phenyl ring, such as 3,4-F2, 3,5-F2, and 3,4-Cl2 (63-65). The 2-pyridyl group in arpromidine was replaced by 3-pyridyl without significant change in H2 agonistic activity, whereas the 4-pyridyl and phenyl analogues were less active. The rank order of potency in the atrium was in good agreement with the positive inotropic effects found in isolated, perfused guinea pig hearts, where 63-65 were the most potent compounds as well.     

Inhibitors of Bacillus subtilis DNA polymerase III. 6-(arylalkylamino)uracils and 6-anilinouracils.

6-(Benzylamino)uracils and substituted 6-anilinouracils have been found to be potent inhibitors of Bacillus subtilis DNA polymerase III by a mechanism identical with that of 6-(phenylhydrazino)uracils. Higher phenylalkylamino homologues are progressively weaker inhibitors of the enzyme. Examination of the effects of substituents on the activity of 6-(benzylamino)uracils against wild-type and mutant enzymes and preliminary results for 6-anilinouracils have permitted further dissection of the mechanism of inhibition. The experimental results indicate that (1) the polymerase inhibitor binding site is compact, accommodating only small alterations in the distance between the uracil and phenyl rings, (2) the phenyl ring, which provides the major contribution to inhibitor-enzyme binding, adopts a specific active conformation, and (3) an enzyme site which interacts with substituents in the phenyl ring forms a part of the active site of DNA polymerase III.     

Synthesis and structure-activity relationships of N-(1-benzylpiperidin-4-yl)arylacetamide analogues as potent sigma1 receptor ligands.

A series of N-(1-benzylpiperidin-4-yl)arylacetamides were synthesized and evaluated for their binding properties for sigma1 and sigma2 receptors. In agreement with previously reported sigma1/sigma2 receptor binding data for N-(1-benzylpiperidin-4-yl)phenylacetamide, all of the N-(1-benzylpiperidin-4-yl)arylacetamide compounds reported below displayed higher affinity for sigma1 vs sigma2 receptors. Replacement of the phenyl ring of the phenylacetamide moiety with a thiophene, naphthyl, or indole aromatic ring had no significant effect on the sigma1 receptor affinity. Replacement of the phenyl ring with an imidazole or pyridyl aromatic ring resulted in a >60-fold loss in affinity for sigma1 receptors and no significant binding affinity for sigma2 receptors. Substitution on the aromatic ring of the benzyl group showed a similar or slightly decreased affinity for sigma1 receptors. Substitution on the aromatic rings of both the phenylacetamide moiety and the benzyl group with a halogen resulted in a similar affinity for sigma(1) receptors and a significantly increased affinity for sigma2 receptors. Comparative molecular field analysis revealed that electrostatic properties of the substituents in the phenylacetamide aromatic ring strongly influenced binding to sigma1 receptors. Compounds 1, 10, 18, 22, 37, and 40 showed the highest selectivity for sigma1 receptors with K(i) (sigma2) to K(i) (sigma(1)) ratios of 100, >92, >122, 77, 74, and 80, respectively. In agreement with previously reported results, the phenylacetamide analogues had no binding affinity for dopamine receptors (D2/D3).