[(3) H]UR-DE257: development of a tritium-labeled squaramide-type selective histamine H2 receptor antagonist.

A series of new piperidinomethylphenoxypropylamine-type histamine H2 receptor (H2 R) antagonists with different substituted "urea equivalents" was synthesized and characterized in functional in vitro assays. Based on these data as selection criteria, radiosynthesis of N-[6-(3,4-dioxo-2-{3-[3-(piperidin-1-ylmethyl)phenoxy]propylamino}cyclobut-1-enylamino)hexyl]-(2,3-(3) H2 )propionic amide ([(3) H]UR-DE257) was performed. The radioligand (specific activity: 63 Ci mmol(-1) ) had high affinity for human, rat, and guinea pig H2 R (hH2 R, Sf9 cells: Kd , saturation binding: 31 nM, kinetic studies: 20 nM). UR-DE257 revealed high H2 R selectivity on membranes of Sf9 cells, expressing the respective hHx R subtype (Ki values: hH1 R: >10000 nM, hH2 R: 28 nM, hH3 R: 3800 nM, hH4 R: >10000 nM). In spite of insurmountable antagonism, probably due to rebinding of [(3) H]UR-DE257 to the H2 R (extended residence time), the title compound proved to be a valuable pharmacological tool for the determination of H2 R affinities in competition binding assays.

Solid-state supramolecular synthesis based on the N-H O heterosynthon: an approach to solve the polymorphism problem in famotidine.

Famotidine (FMT), a histamine H2 -receptor antagonist, is a drug commonly used in treatments of gastroesophageal diseases that presents solid-state polymorphism (A and B forms), the marketed form being the metastable polymorph B. A new stable salt was obtained by combination of FMT and maleic acid as coformer. FMT maleate (FMT-MLT) was prepared either by solvent evaporation or comilling methods. Single-crystal X-ray diffraction reveals that (FMT)(+) in FMT-MLT adopts an extended conformation that is stabilized by classical and nonclassical H-bonds. The three-dimensional packing consists of tapes along the axis b that further develop a columnar array based on H-bonds involving (FMT)(+) side chain. Nonconventional π-stacking interactions between adjacent tapes were also identified. Fourier transform infrared, differential scanning calorimetry, thermogravimetric analysis, polarized light thermal microscopy, and scanning electron microscopy were employed to characterize the multicomponent complex. According to the solubility values in water and simulated gastric fluid, FMT-MLT exhibits such a performance that improves on the solubility of the commercially available polymorph. Finally, the higher stability of FMT-MLT regarding both FMT forms, as well as its easy preparation from either A or B forms or a mixture of them, also allows to consider this salt as a valuable alternative to avoid the polymorphism issue in marketed formulations containing FMT.

Synthesis and dual histamine H1 and H2 receptor antagonist activity of cyanoguanidine derivatives.

Premedication with a combination of histamine H1 receptor (H1R) and H2 receptor (H2R) antagonists has been suggested as a prophylactic principle, for instance, in anaesthesia and surgery. Aiming at pharmacological hybrids combining H1R and H2R antagonistic activity, a series of cyanoguanidines 14-35 was synthesized by linking mepyramine-type H1R antagonist substructures with roxatidine-, tiotidine-, or ranitidine-type H2R antagonist moieties. N-desmethylmepyramine was connected via a poly-methylene spacer to a cyanoguanidine group as the "urea equivalent" of the H2R antagonist moiety. The title compounds were screened for histamine antagonistic activity at the isolated ileum (H1R) and the isolated spontaneously beating right atrium (H2R) of the guinea pig. The results indicate that, depending on the nature of the H2R antagonist partial structure, the highest H1R antagonist potency resided in roxatidine-type compounds with spacers of six methylene groups in length (compound 21), and tiotidine-type compounds irrespective of the alkyl chain length (compounds 28, 32, 33), N-cyano-N'-[2-[[(2-guanidino-4-thiazolyl)methyl]thio]ethyl]-N″-[2-[N-[2-[N-(4-methoxybenzyl)-N-(pyridyl)-amino] ethyl]-N-methylamino]ethyl] guanidine (25, pKB values: 8.05 (H1R, ileum) and 7.73 (H2R, atrium) and the homologue with the mepyramine moiety connected by a six-membered chain to the tiotidine-like partial structure (compound 32, pKB values: 8.61 (H1R) and 6.61 (H2R) were among the most potent hybrid compounds. With respect to the development of a potential pharmacotherapeutic agent, structural optimization seems possible through selection of other H1R and H2R pharmacophoric moieties with mutually affinity-enhancing properties.

Phenoxypropylamines: synthesis and antiulcer evaluation.

We have synthesized a number of phenoxypropylamines from N-{3-[3-(1-piperidinylmethyl)phenoxy]propyl}chloroacetamide (3). All the products have been characterized by elemental analysis, (1)H-NMR and MS. The biological activity effects of the title compounds were examined. From the biological activity results, we found that two of themshowed significant gastric acid antisecretory activity.

Photoaffinity labeling of the anionic sites in Caco-2 cells mediating saturable transport of hydrophilic cations ranitidine and famotidine.

The H(2) antagonists, ranitidine and famotidine, exhibit saturable absorptive transport across Caco-2 cell monolayers and human intestine via a yet unidentified mechanism. A photoreactive derivative of famotidine has been synthesized and evaluated as a photoaffinity probe for the putative transporter protein(s). The probe irreversibly inhibited ranitidine transport across Caco-2 cell monolayers and irreversibly increased the transepithelial electrical resistance (TEER) after UV activation. Photoaffinity labeling was protected by a molar excess of famotidine.

Synthesis and pharmacological activity of fluorescent histamine H2 receptor antagonists related to potentidine.

Fluorescently labeled histamine H(2) receptor antagonists were synthesized starting from N-cyano-N'-[3-(3-piperidin-1-ylmethylphenoxy)propyl]guanidines with an additional N"-omega-aminoalkyl substituent (chain lengths 2-8 methylene groups) or from 3-(3-piperidin-1-ylmethylphenoxy)propylamine. The primary amino group was derivatized with various fluorophores (fluorescein, acridine, dansyl, nitrobenzoxadiazole (NBD), indolo[2,3-a]quinolizine). On the isolated spontaneously beating guinea pig right atrium most of the fluorescent probes were only weakly active, however, the NBD-labeled substances proved to be potent histamine H(2) receptor antagonists achieving pA(2) values in the range of 7.5-8.0, comparable to the activity of famotidine.

Anti-Helicobacter pylori agents. 5. 2-(Substituted guanidino)-4-arylthiazoles and aryloxazole analogues.

To extend the SAR study of guanidinothiazoles as a structurally novel class of anti-H. pylori agents, a series of 2-(substituted guanidino)-4-arylthiazoles and some 4-aryloxazole analogues were synthesized and evaluated for antimicrobial activity against H. pylori. Some of them were also subjected to H2 antagonist and gastric antisecretory assays. Several arylthiazoles were identified as potent anti-H. pylori agents, and of these, thienylthiazole derivative 44 exhibited the strongest activity (MIC = 0.0065 microg/mL) among the compounds obtained in our guanidinothiazole studies. Although 44 was void of H2 antagonist activity, pyridylthiazole derivative 39 had both potent anti-H. pylori and H2 antagonist activities. Thiazolylthiazole derivative 46 also showed potent anti-H. pylori activity, but the H2 antagonist activity was weak. On the other hand, no attractive activities were found in pyrimidyl, oxazolyl, isoxazolyl, imidazolyl, and oxadiazolylthiazole derivatives. The anti-H. pylori activity of the aryloxazole analogues was weaker than those of the corresponding arylthiazole derivatives, though they had potent H2 antagonist activity.

Anti-Helicobacter pylori agents endowed with H2-antagonist properties.

New anti-Helicobacter pylori (H. pylori) agents endowed with H2-antagonists properties were obtained by combining the lamtidine derived pharmacophoric group with the antibiotic calvatic acid. All the compounds were tested for their irreversible H2-antagonist properties and for their ability to inhibit 20 H. pylori strains, two of them metronidazole resistant. The most active derivative (compound 4) displayed antimicrobial activity similar to metronidazole.

Anti-Helicobacter pylori agents. 4. 2-(Substituted guanidino)-4-phenylthiazoles and some structurally rigid derivatives.

In order to find a new class of anti-Helicobacter pylori (H. pylori) agents, a series of 4-[(3-acetamido)phenyl]-2-(substituted guanidino)thiazoles and some structurally rigid analoges were synthesized and evaluated for antimicrobial activity against H. pylori. Among the compounds obtained, high anti-H. pyrori activities were observed in benzyl derivative 34 (MIC = 0.025 microg/mL) and phenethyl derivatives 35 and 36 (MIC = 0.037 microg/mL and 0.017 microg/mL). Though alkyl derivatives generally showed lower activity, the 2-methoxyethyl derivative 28 preserved significant activity (MIC = 0.32 microg/mL) and also exhibited more potent gastric antisecretory activity than ranitidine. Structural restriction by bridging between the thiazole and the phenyl rings with an alkyl chain did not improve the activity in this series.

Anti-Helicobacter pylori agents. 3. 2-[(Arylalkyl)guanidino]-4-furylthiazoles.

A series of 2-[(arylalkyl)guanidino]-4-[(5-acetamidomethyl)furan-2-yl]thiazole s and some 4-acetamidomethyl positional isomers were synthesized and evaluated for antimicrobial activity against Helicobacter pylori. Among the compounds that had potent antimicrobial activity (MIC < 0. 1 microgram/mL), compounds 31 and 36 additionally possessed H2 antagonist and gastric antisecretory activities. Though compound 51, an analogue incorporating a methyl group onto the furan nucleus of 36, and compound 54, a positional isomer of 51, also showed potent anti-H. pylori activity, the H2 antagonism profile was eliminated from these compounds. Thus, two types of potent anti-H. pylori agents could be derived from the same scaffold.

Combined histamine H1/H2 receptor antagonists: part I. Pharmacological hybrids with pheniramine- and roxatidine-like substructures.

A series of hybrid compounds combining the pharmacophores of both pheniramine-type histamine H1 receptor antagonists and roxatidine-type H2 receptor antagonists have been synthesized and tested for histamine antagonism at the isolated ileum (H1) and the spontaneously beating right atrium (H2) of the guinea pig. The 'polar group' of the H2 antagonist moiety (cyanoguanidine, nitroethenediamine or urea) and the side chain amino group of the H1 antagonist portion have been linked by a polymethylene spacer or by a piperazine system. The incorporation of a flexible spacer (2-7 methylene groups) resulted in H1 antagonists achieving up to 2.4 times the activity of pheniramine. Depending on the nature of the polar group the highest H2 antagonist potency resides in compounds with spacers ?2 methylene groups. Nitroethenediamine 24c with a seven-membered chain and a chlorpheniramine substructure proved to be approximately equipotent with pheniramine at the H1 and with ranitidine at the H2 receptor (pKB values 7.82 and 7.1, respectively).

Combined histamine H1/H2 receptor antagonists: part II. Pharmacological hybrids with pheniramine- and tiotidine-like substructures.

Hybrid molecules combining the crucial structural features of both pheniramine-type histamine H1 receptor antagonists and guanidinothiazole-type H2 receptor antagonists have been synthesized and tested for in vitro pharmacological activity at the isolated ileum and the spontaneously beating right atrium of the guinea-pig. In the title compounds the basic side chain nitrogen of the H1 antagonist and the so-called 'polar group' (cyanoguanidine, urea, or nitroethenediamine) of the H2 antagonist moiety have been linked by a polymethylene spacer. The new substances displayed high affinities to both histamine receptor subtypes and a dual type of antagonism (surmountable/insurmountable) characterized by a shift of the concentration response curves to the right accompanied by a depression of the maximal response to the agonist if the antagonist concentration was >/=100 nM. Highest combined histamine antagonist activities were found in the nitroethenediamine series with pKB values ranging from 8.16 to 9.04 in the ileum (H1) and 7.0-8.08 in the atrium (H2)

A novel histamine 2(H2) receptor antagonist with gastroprotective activity. I. Synthesis and pharmacological evaluation of N-phenoxypropylacetamide derivatives with thioether function.

In an attempt to develop new types of anti-ulcer agents, a series of N-(phenoxypropyl)acetamide derivatives with a thioether moiety and their sulfur-oxidized analogues were synthesized and evaluated for histamine H2-receptor antagonistic activity, Ca antagonistic activity and gastric anti-secretory activity in the lumen-perfuseed rat. Selected compounds were also tested for gastroprotective activity, which was expected to be based on Ca antagonistic activity. Structure-activity relationships are discussed. As a thioether moiety, -CH2-S(O)p-CH2-Ar (Ar; phenyl or furyl) was found to be optimal for the above activities. Especially, N-[3-[(3-(piperidinomethyl) phenoxy]propyl]acetamide with a benzyl sulfinyl, benzylsulfonyl, furfurylsulfinyl or furfurylsulfonyl group showed potent gastroprotective activity upon oral administration in a rat model. These compounds are candidates for novel anti-ulcer drugs with gastric anti-secretory and gastroprotective activities. 2-Furfurylsulfinyl-N-[3-[(piperidinomethyl)phenoxy]propyl]ac etamide was the most potent among the compounds tested and was given the code designation FRG-8701.

A novel histamine 2(H2) receptor antagonist with gastroprotective activity. II. Synthesis and pharmacological evaluation of 2-furfuryl-thio and 2-furfurylsulfinyl acetamide derivatives with heteroaromatic rings.

We recently found that N-[3-[3-(piperidinomethyl)phenoxyl]propyl]acetamide derivatives with a thioether function showed gastric anti-secretory and gastroprotective activities and that the thioether function (particularly furfurylthio or furfurylsulfinyl) was essential for gastroprotection. In the present study, a series of 2-furfurylthio and 2-furfurylsulfinyl acetamide derivatives were synthesized and evaluated for histamine H2 receptor antagonistic activity, gastric anti-secretory activity and gastroprotective action. Based on the structure of N-[3-[3-(piperidinomethyl)phenoxyl]propyl]acetamide, we designed compounds, in which the 3-(piperidinomethyl)phenoxy part is substituted with many types of heteroaromatic ring attached to the tertiary amine and the propyl group is replaced with other carbon linkages. Structure-activity relationships are discussed. 2-Furfurylsulfinyl-N-[4-[4-(piperidinomethyl)-2-pyridylox y]- (Z)-2-butenyl]acetamide was the most potent among the tested compounds and was given the code designation FRG-8813.

[Synthesis and antiulcer activity of N-2-(2-hydroxy-2-phenyl)ethyl-N"-(methanesulfonyl)guanidine analogue of ranitidine. Development of a new antiulcer agent T-593].

A series of the aryl-substituted N'-2-(2-hydroxy-2-phenyl)ethyl derivatives of N"-methanesulfonyl-N-2-((5-dimethylaminomethyl or 5-methylaminomethyl) furfurylthio)ethylguanidine have been synthesized as potential antisecretory and mucosal protective antiulcer agents. The synthetic routes involves, at the last stage, the reaction of 2-hydroxy-2-phenylethylamines with N-2-(furfurylthio)-ethyl-N'-methanesulfonyl-S-methylisothiourea or its O-phenylisourea counterpart. The primary screening test to assess the inhibitory activity of the synthetic compounds on histamine-induced gastric acid secretion was carried out in anesthetized rats by the lumen-perfusion technique of Ghosh and Schild and also by the pylorus-ligated preparation method. The best profile of histamine H2-antagonist activity was much better than that of the prototype ranitidine, and obtained with N'-(2-(2-hydroxy-2-(4-hydroxyphenyl)) ethyl-N"-methanesulfonyl-N-2-(5-(methylaminomethyl)furfurylthio)et hylguanidine (12f), which was also characterized by enhancing the gastric mucosal blood flow in rabbits as observed by the thermoelectric method. This compound 12f, designated as T-593, significantly inhibited the formation of the indomethacin-induced gastric lesions in rats; 3.5-fold more potent than ranitidine, but 4-fold less active than famotidine. On the other hand, T-593 and famotidine displayed comparable activities in healing the acetic acid-induced gastric ulcer with and without the dosing of indomethacin. Additional notable features of T-593, as determined in rats, are that its protective effect on the hemorrhagic shock-induced lesion under the prior dosing of histamine is ca. 10- and 2-fold greater than ranitidine and famotidine, respectively, and that a decrease in the gastric mucosal blood flow caused by a partial blood-withdrawal is more strongly recovered with T-593 than with famotidine. These experimental results suggest that the antiulcer efficacy of T-593 can be explained by its dual activities: antisecretion of gastric acid and, more importantly, protection of gastric mucous membrane.

Anti-Helicobacter pylori agents. 2. Structure activity relationships in a new series of 2-alkylguanidino-4-furylthiazoles.

SAR for antimicrobial activity against H. pylori was investigated in a new series of 2-alkylguanidino-4-furylthiazoles. Of the compounds obtained, cyclohexylmethyl and ethoxyethyl derivatives were identified as a novel class of anti-H. pylori agents which possessed potent and selective antimicrobial activity against H. pylori. These compounds also showed gastric antisecretory activity.

Indenopyridazinone derivatives as potential antisecretory and antiulcer agents.

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.

Anti-Helicobacter pylori agents. 1. 2-(Alkylguanidino)-4-furylthiazoles and related compounds.

A series of 2-(alkylguanidino)-4-[5-(acetamidomethyl)furan-2-yl]thiazoles and related compounds were synthesized and evaluated for antimicrobial activity against Helicobacter pylori, inhibitory effect on gastric acid secretion, and histamine H2-receptor antagonist activity. Introduction of alkyl substituents on the guanidino moiety resulted in a significant increase in antimicrobial activity, which was associated with the alkyl chain length. Of the compounds obtained, the n-hexylguanidino derivative 13 demonstrated a 250-fold improvement in activity (MIC = 0.11 micrograms/mL) over the unsubstituted guanidino derivative 7. Alkyl-substituted guanidino derivatives also displayed gastric antisecretion and H2-antagonist activities. However, a simple correlation between the alkyl chain length and the activities was not found in these assays. Replacement of the guanidine with other bioisosteric groups (thiourea, urea, or (dimethylamino)methyl) resulted in loss of all activities tested. Thus the guanidino moiety was found to be essential for activity in this series of compounds.

Synthesis and structure-activity relationships of dual histamine H2 and gastrin receptor antagonists with decreased hydrophobicity.

In order to study structure-activity relationships of the previously reported dual histamine H2 and gastrin receptor antagonists and also to improve their low oral absorbability, we tried two chemical modifications. One tried to decrease the high hydrophobicity of the parent hybrid compounds to an appropriate level by incorporating a hydrophilic group into the molecule and the other by replacing the more hydrophobic groups with less hydrophobic ones. The former compounds (type I) involved hybrid compounds with a hydroxyl group at a position of a spacer, a piperidine moiety of H2A, or a phenyl ring at the C5 of the benzodiazepine skeleton as well as those with a free carboxyl group in the piperidine moiety of H2A. The latter (type II) involved hybrid compounds with the C5-phenyl group replaced with either a methyl group or hydrogen atom. Among them, only a type I compound, ([2-[3-(3-piperidin-1-ylmethylphenoxy)propylcarbamoyl] ethylcarbamoyl]methyl)carbamic acid 3-[3-[5-(3-hydroxyphenyl)-1-methyl-2-oxo-2,3-dihydro-1H-1,4-benzodiaz epin-3-yl]ureido]benzyl ester (18), showed potent dual histamine H2 and gastrin receptor antagonistic activity, whereas others resulted in a significant decrease of histamine H2 receptor antagonistic activity. The in vivo gastric acid antisecretory activity of 18 evaluated by Schild's rat method, however, did not suggest any notable improvement in oral absorbability.

Synthesis and structure-activity relationships of dual histamine H2 and gastrin receptor antagonists with modified benzodiazepine skeletons.

Three different types of dual histamine H2 and gastrin receptor antagonists, e.g. those bearing a benzazepine, benzoxazepine, or benzothiazepine skeleton instead of the benzodiazepine one as a gastrin receptor antagonistic moiety were synthesized to reduce high hydrophobicity of parent compounds and evaluated for the dual activities. These skeletal modifications significantly potentiated the binding affinity of dual antagonists with histamine H2 receptor but markedly diminished their binding affinity with the gastrin receptor and the gastrin versus CCK-A receptor selectivity. We evaluated in vivo gastric acid antisecretory activities for some representative compounds by the rat pylorus ligation method for 10 mg kg(-1) dose by oral route. However, they exerted only low inhibitory activities for oral dose with % inhibition values ranging between 32 and 53%.