Effect of 3-[p-(trans-4-aminomethylcyclohexylcarbonyl)-phenyl] propionic acid hydrochloride on gastric mucosal blood flow

The effects of 3-[p-(trans-4-aminomethylcyclohexylcarbonyl)phenyl]propionic acid hydrochloride (TEI-5103, TG-51) on gastric mucosal blood flow (GMBF) in rats, rabbits, and dogs were studied by using hydrogen gas clearance, cross-thermocouple, and 51Cr-labelled erythrocyte methods. TEI-5103 (5 mg/kg i.v.) increased GMBF, measured by hydrogen gas clearance method, in anesthetized rats. At 1-10 mg/kg i.v. it also increased GMBF, measured by cross-thermocouple method, in anesthetized rabbits and dogs. The increasing effect of TEI-5103 was more potent than that of cetraxate. By the intragastric route, TEI-5103 (400 mg/kg) increased the GMBF 1 h after the administration in anesthetized and pylorus-ligated rats. Anti-ulcer doses of TEI-5103 prevented the decrease in the GMBF induced by serotonin or indomethacin in anesthetized rats. The drug also prevented the decrease in gastric mucosal blood volume induced by serotonin. The increase in dog femoral arterial blood flow by TEI-5103 (1-10 mg i.a.) was not affected by propranolol, atropine, diphenhydramine, or aminophylline, nor was it attenuated by pretreatment with indomethacin. TEI-5103, like papaverine, inhibited Ca2+-, PGF2 alpha- and norepinephrine-induced contractions of isolated rabbit coeliac artery. The results indicate that TEI-5103 increases GMBF by acting directly on the gastric microcirculation and that this increasing effect may contribute to the anti-ulcer activity of TEI-5103.     

Effect of 3-[p-(trans-4-aminomethylcyclohexylcarbonyl)phenyl] propionic acid hydrochloride on gastric mucosa directly from the lumen

The present experiments were designed to determine if the novel anti-ulcer drug 3-[p-(trans-4-aminomethylcyclohexylcarbonyl)phenyl]propionic acid hydrochloride (TEI-5103, TG-51), acts on the gastric mucosa directly from the lumen when given orally. TEI-5103 given orally (50-400 mg/kg) prevented the lesion formation induced by 0.1N HCl + 60% ethanol, but when given intraperitoneally (50-200 mg/kg) or intravenously (40 mg/kg), it did not prevent the formation of lesions. Indomethacin-induced gastric lesions were inhibited by oral administration of TEI-5103, but not by intraduodenal administration. In pylorus-ligated rats, TEI-5103 given intragastrically also inhibited the development of gastric lesions induced by HCl + ethanol. These results suggest that the presence of TEI-5103 in the stomach is necessary to elicit its anti-ulcer effect. In microautoradiographic examination, silver grains corresponding to [14C]-TEI-5103 distributed in the upper part of the mucosa (luminal side) at 0.5 to 4 h after the oral administration. However, when given intraduodenally or intravenously, this high concentration of [14C]-TEI-5103 was not observed in the stomach tissue. When given orally, the content of [14C]-TEI-5103 in rat stomach tissue was about 100 times higher than that in plasma and the time course of distribution was different from that seen in the gastric content. From these results, it seems that TEI-5103 distributes in the gastric mucosa directly from the lumen. In conclusion, TEI-5103, when given orally, distributes in the gastric mucosa as a target issue directly from the lumen; and only the oral and gastric route of administration lead to the anti-ulcer effect.     

Anti-ulcer effect of 3-[p-(trans-4-aminomethylcyclohexylcarbonyl) phenyl] propionic acid hydrochloride (TEI-5103)

The anti-ulcer effects of the newly synthesized compound 3-[p-(trans-4-aminomethylcyclohexylcarbonyl)-phenyl]propionic acid hydrochloride (TEI-5103) on experimentally induced ulcers in rats were studied. TEI-5103 at doses of 25 to 400 mg/kg p.o. prevented formation of ulcers induced by serotonin, indomethacin, acetylsalicylic acid or stress (acute ulcer models), its effect being greater against gastric ulcers induced by serotonin. On acetic acid ulcer (chronic ulcer model), TEI-5103 at a daily dose of 200 mg/kg p.o. accelerated the healing of ulcers. TEI-5103 at doses of 100 to 400 mg/kg i.d. did not inhibit gastric acid secretion in pylorus-ligated rats. It markedly increased gastric blood flow in anesthetized rats (at 10-20 mg/kg i.v., measured by the aminopyrine clearance method), and also increased gastric blood flow in anesthetized dogs (at 2.5-10 mg/kg i.v., measured by the cross thermocouple method). These results indicate that TEI-5103 is effective as an anti-ulcer agent increasing gastric mucosal blood flow and possibly promoting the healing process of peptic ulcers.     

Effect of (+/-)-2-[p-(2-thenoyl)phenyl] propionic acid (suprofen) on experimental allergic reactions

The effects of (+/-)-2-[p-(2-thenoyl)phenyl] propionic acid (suprofen), a new anti-inflammatory agent, on experimental allergic reaction and antibody formation were examined. The action was compared with those of ketoprofen, ibuprofen, indomethacin, tranilast, chlorpheniramine, prednisolone and/or cyclophosphamide. Suprofen inhibited homologous PCA in rats, immunological histamine release from rat peritoneal mast cells and guinea pig lung tissues, Forssman cutaneous vasculitis (FCV) and the Arthus reaction in guinea pigs. The potency for inhibition of the PCA reaction was similar to that of ketoprofen and more potent than ibuprofen and trailast. As for the release of anaphylactic mediators, suprofen was less potent than tranilast in terms of histamine release, but not the release of the slow reacting substance of anaphylaxis (SRS-A). Suprofen inhibited FCA more potently than other nonsteroidal anti-inflammatory drugs (NSAID). The inhibition of the Arthus reaction by suprofen was similar to those of other NSAID and prednisolone. Suprofen hardly affected delayed hypersensitivity in guinea pigs and antibody (IgM or IgE) formation in mice or rats.     

The modes of anti-inflammatory and analgesic actions of 2-[4-(3-methyl-2-butenyl) phenyl] propionic acid (TA-60) and 2-[4-(2,2-dichlorovinyl) phenyl] propionic acid (TA-668) and effect of TA-60 on the gastrointestinal tract

TA-668 and TA-60, potent anti-inflammatory compounds, showed no inhibition against the dextran-, the serotonin- and the carrageenin + prostaglandin E2 (PGE2)-induced hind paw edemas in rats and neither did typical acidic non-steroidal anti-inflammatory drugs (ANSAIDs) such as indomethacin. On the other hand, salicylic acid, mepirizole and tiaramide X HCl inhibited the hind paw edema induced by carrageenin + PGE2 in rats. TA-668 and TA-60 as well as other ANSAIDs inhibited the arachidonic acid (AA)-induced erythema, but did not inhibit the PGE2-induced erythema. Mepirizole and tiaramide X HCl showed no inhibition against both the AA- and the PGE2-induced erythemas. TA-668 and TA-60 showed analgesic activities in the adjuvant-induced hind paw edematous rats. The analgesic activities of these compounds disappeared when PGE2 was injected into the inflamed paw as well as indomethacin and ibuprofen. It is concluded that anti-inflammatory and analgesic activities of both TA-668 and TA-60 were based on the inhibition of cyclo-oxygenase. TA-60 showed a protective effect against gastric necrosis induced by necrotizing agents such as HCl, NaOH or NaOH + EtOH. TA-60 showed about a 4 times less potent activity than ibuprofen in delay of occurring time of castor oil-induced diarrhea in rats. These results suggest that the slight ulcerating effect of TA-60 on the gastrointestinal tract might be attributed to its gastric protective effect and slight decreasing effect on the gastrointestinal level of PGE2.     

Synthesis of hexaprofen [2-(4-cyclohexylphenyl) propionic acid]

A novel preparative method for hexaprofen, which is a potent antiinflammatory agent, is described. Friedel-Crafts reaction of cyclohexylbenzene with ethyl α-chloro-α-(methylthio) acetate1 and α-chloro-α-(methylthio) acetonitrile2 afforded ethyl 2-(methylthio)-2-(4-cyclohexylphenyl) acetate7 and 2-methylthio-2-(4-cyclohexylphenyl) acetonitrile8, respectively. Compounds7 and8 were converted into the corresponding ethyl 2-methylthio-2-(4-cyclohexylphenyl) propionate9 and 2-methylthio-2-(4-cyclohexylphenyl) propionitrile10 by methylation with sodium hydride and methyl iodide. Hexaprofen13 was prepared by hydrolysis of ethyl 2-(4-cyclohexylphenyl) propionate11 and of 2-(4-cyclohexylphenyl) propionitrile12 followed by desulfurization of compounds9 and10.     

Synthesis and antitumor activity of 4-[p-[bis(2-chloroethyl)amino]phenyl]butyrates

Ten 4-[p-[bis(2-chloroethyl)amino]phenyl]butyrates were synthesized and evaluated for antitumor activity. The 2-phenoxyethyl ester exhibited activity against P-388 lymphocytic leukemia, and the n-butyl and n-pentyl esters exhibited activity against L-1210 lymphoid leukemia in initial screening tests.     

Preparation and biodistribution of 1-[2-(3-[125I]iodo-4-aminophenyl)ethyl]-4-[3-(trifluoromethyl) phenyl]piperazine and 1-[2-(3-[125I]iodo-4-azidophenyl)ethyl]-4-[3-(trifluoromethyl)phenyl] piperazine

The iodinated analogue of 1-[2-(4-aminophenyl)ethyl]-4-[3-(trifluoromethyl)phenyl]piperazine (PAPP), IPAPP (4), and the corresponding azido compound azido-IPAPP (5) were synthesized. The corresponding no-carrier-added 125I (T1/2 = 60 days, 35-60 keV) labeled compounds were also prepared. High specific binding was observed from in vitro binding studies using rat brain tissue preparation; Ki = 20 and 17.5 nM against [3H]-5-HT. In vivo biodistribution studies in rats showed that azido-[125I]IPAPP passed through intact blood-brain barrier and localized in the brain. Ex vivo autoradiography of rat brain sections exhibited a diffuse uptake pattern, which may be due to specific and nonspecific binding. The results indicate that IPAPP and azido-IPAPP may not be suitable to image the serotonin receptor in the brain.     

Identification of human cytochrome P450 isoforms involved in the metabolism of S-2-[4-(3-methyl-2-thienyl)phenyl]propionic acid

1. To identify the cytochrome P450 (CYP) isoenzymes responsible for the major metabolic pathways of S-2-[4-(3-methyl-2-thienyl)phenyl] propionic acid (S-MTPPA) in man, the metabolism of S-MTPPA was examined using human liver microsomes and microsomes containing cDNA-expressed CYP isozymes (CYP1A2, 2A6, 2B6, 2C9-Arg, 2C9-Cys, 2C19, 2D6-Val, 2E1 and 3A4). 2. S-MTPPA was mainly oxidized to the 5-hydroxylated metabolite of the thiophene ring (MA6) with human liver microsomes in the presence of NADPH. The formation of MA6 was inhibited by SKF 525-A, suggesting that CYP plays role in the formation of MA6. 3. Eadie-Hofstee plots for the 5-hydroxylation of S-MTPPA in the range 5-100 μM were linear for all samples studied, suggesting that the formation of MA6 by human liver microsomes follows simple Michaelis-Menten kinetics. Apparent V_max = 1.42±0.64 nmol/min/mg protein; K_m = 12±5 μM. 4. Among the CYP inhibitors examined (α-naphthoflavone, sulphaphenazole, omeprazole, quinidine and troleandomycin), sulphaphenazole (a CYP2C9 inhibitor) showed the most potent inhibitory effect on the 5-hydroxylation of S-MTPPA by human liver microsomes. 5. When incubated with microsomes containing cDNA-expressed CYP isozymes, S-MTPPA was substantially oxidized to MA6 only by CYP2C9. 6. These results suggest that formation of the major metabolite of S-MTPPA, MA6, in human liver microsomes is catalysed predominantly by a single CYP isoenzyme, namely CYP2C9.     

Discovery of a potent, orally bioavailable beta(3) adrenergic receptor agonist, (R)-N-[4-[2-[[2-hydroxy-2-(3-pyridinyl)ethyl]amino]ethyl]phenyl]-4-[4 -[4-(trifluoromethyl)phenyl]thiazol-2-yl]benzenesulfonamide

As part of our investigation into the development of orally bioavailable beta(3) adrenergic receptor agonists, we have identified a series of pyridylethanolamine analogues possessing a substituted thiazole benzenesulfonamide pharmacophore that are potent human beta(3) agonists with excellent selectivity against other human beta receptor subtypes. Several of these compounds also exhibited an improved pharmacokinetic profile in dogs. For example, thiazole sulfonamide 2e (R = 4-F(3)C-C(6)H(4)) is a potent full beta(3) agonist (EC(50) = 3.6 nM, 94% activation) with >600-fold selectivity over the human beta(1) and beta(2) receptors, which also displays good oral bioavailability in several mammalian species, as well as an extended duration of action.     

Pharmacological studies on the TXA2 synthetase inhibitor (E)-3-[p-(1H-imidazol-1-ylmethyl)phenyl]-2-propenoic acid (OKY-046)

The effects of (E)-3-[p-(1H-imidazol-1-ylmethyl)phenyl]-2-propenoic acid (OKY-046) on thromboxane A2 (TXA2) synthetase in vitro and on experimental animal models of sudden death and cerebral infarction were studied. IC50 values of OKY-046 for the TXA2 synthetase of human, rabbit, dog and guinea pig washed platelets were 0.004, 0.004, 0.26 and 2.4 microM, respectively. OKY-046 at concentrations up to 1 mM, however, did not inhibit prostacyclin (PGI2) synthetase from bovine aorta microsomes or cyclooxygenase and PGE2 isomerase from sheep seminal vesicle microsomes. Similarly, platelet 12-lipoxygenase was not affected by OKY-046. Evidence for a re-direction of arachidonate metabolism from thromboxane synthesis toward PGI2 synthesis was obtained using rat peritoneal cells. Namely, OKY-046 increased PGI2 production accompanied by an inhibition of TXA2 production at a concentration of more than 1 microM. OKY-046 at a dose of 0.1 mg/kg (i.v.) in dogs inhibited the aortic and mesenteric arterial contraction of rabbit induced by the addition of arachidonate to extracorporated blood of the dogs. OKY-046 at a dose of 0.3 mg/kg (i.v.) prevented the arachidonate-induced sudden death and also decreased the incidence of cerebral infarction induced by injection of arachidonate into the internal carotid artery in rabbits. Aspirin also decreased the incidence of cerebral infarction at a dose of 30 mg/kg (i.v.). These results suggest that OKY-046 may be valuable for the treatment of cerebrovascular and cardiovascular diseases associated with vasoconstriction and thrombosis due to TXA2.     

Discovery of two clinical histamine H(3) receptor antagonists: trans-N-ethyl-3-fluoro-3-[3-fluoro-4-(pyrrolidinylmethyl)phenyl]cyclobutanecarboxamide (PF-03654746) and trans-3-fluoro-3-[3-fluoro-4-(pyrrolidin-1-ylmethyl)phenyl]-N-(2-methylpropyl)cyclobutanecarboxamide (PF-03654764)

The discovery of two histamine H(3) antagonist clinical candidates is disclosed. The pathway to identification of the two clinical candidates, 6 (PF-03654746) and 7 (PF-03654764) required five hypothesis driven design cycles. The key to success in identifying these clinical candidates was the development of a compound design strategy that leveraged medicinal chemistry knowledge and traditional assays in conjunction with computational and in vitro safety tools. Overall, clinical compounds 6 and 7 exceeded conservative safety margins and possessed optimal pharmacological and pharmacokinetic profiles, thus achieving our initial goal of identifying compounds with fully aligned oral drug attributes, "best-in-class" molecules.     

Pharmacological studies of dl-2[3-(2'-chlorophenoxy)phenyl]propionic acid. I. Analgesic and antipyretic effects

Analgesic and antipyretic effects of dl-2[3-(2'-chlorophenoxy)phenyl] propionic acid (CPP) were studied in mice, rats and guinea-pigs. CPP produced a dose dependent inhibition of acetic acid-induced writhing syndrome. Its ED50 values 1 and 3 hr after oral administration were 47 and 31 mg/kg, respectively. CPP had a potent analgesic effect on bradykinin-induced nociceptive response in rats, and its ED50 value was 15 mg/kg 2 hr after oral administration. The analgesic activity of CPP in these experiments was less potent than that of indomethacin, but it was approximately equivalent to ibuprofen and 10 to 20 times as potent as aspirin. CPP had no analgesic effect on both the tail pinch and hot plate tests in mice, while CPP potentiated the analgesic effect of codeine on these tests. CPP had no effect on the nociceptive response induced by intradermal injection of bradykinin and/or EDTA in guinea-pigs. On the other hand, when CPP was given orally in a dose range of 1.25 to 5 mg/kg, it produced an antipyretic effect on yeast-induced fever in rats. The antipyretic activity of CPP was equivalent to ibuprofen and 10 to 15 times as potent as aspirin.     

Identification of human cytochrome P450 isoforms involved in the metabolism of S-2-[4-(3-methyl-2-thienyl)phenyl]propionic acid.

1. To identify the cytochrome P450 (CYP) isoenzymes responsible for the major metabolic pathways of S-2-[4-(3-methyl-2-thienyl)phenyl] propionic acid (S-MTPPA) in man, the metabolism of S-MTPPA was examined using human liver microsomes and microsomes containing cDNA-expressed CYP isozymes (CYP1A2, 2A6, 2B6, 2C9-Arg, 2C9-Cys, 2C19, 2D6-Val, 2E1 and 3A4). 2. S-MTPPA was mainly oxidized to the 5-hydroxylated metabolite of the thiophene ring (MA6) with human liver microsomes in the presence of NADPH. The formation of MA6 was inhibited by SKF 525-A, suggesting that CYP plays role in the formation of MA6. 3. Eadie-Hofstee plots for the 5-hydroxylation of S-MTPPA in the range 5-100 microM were linear for all samples studied, suggesting that the formation of MA6 by human liver microsomes follows simple Michaelis-Menten kinetics. Apparent Vmax = 1.42+/-0.64 nmol/min/mg protein; Km = 12+/-5 microM. 4. Among the CYP inhibitors examined (alpha-naphthoflavone, sulphaphenazole, omeprazole, quinidine and troleandomycin), sulphaphenazole (a CYP2C9 inhibitor) showed the most potent inhibitory effect on the 5-hydroxylation of S-MTPPA by human liver microsomes. 5. When incubated with microsomes containing cDNA-expressed CYP isozymes, S-MTPPA was substantially oxidized to MA6 only by CYP2C9. 6. These results suggest that formation of the major metabolite of S-MTPPA, MA6, in human liver microsomes is catalysed predominantly by a single CYP isoenzyme, namely CYP2C9.     

3-(4-甲磺酰基)苯基-2-环己基-2-丁烯酸-γ-内酯的合成

目的　设计并合成了标题化合物。方法　以对甲磺酰基苯乙酮为原料,经溴代、缩合和环合三步反应合成了产物。结果　总收率为82.5%,中间体和产物经核磁共振谱和质谱确证。结论　成功地合成了设计的化合物,而且摸索了反应条件,使反应具有时间短,收率高等优点。     

Effects of the new H2-receptor antagonist 3-amino-4-[4- [4- (1-piperidinomethyl)-2-pyridyloxy]-cis-2-butenylamino]-3-cyclobutene-1, 2- dione hydrochloride on gastric acid secretion and ulceration

The effect of 3-amino-4-[4-[4-(1-piperidinomethyl)-2-pyridyloxy]-cis- 2-butenylamino]-3-cyclobutene-1,2-dione hydrochloride (IT-066), a new H2-receptor antagonist, on gastric acid secretion and on various experimental ulcers was investigated. IT-066 showed very potent and long lasting antisecretory action in pylorus ligated rats. The inhibitory potency of IT-066 given subcutaneously for gastric acid secretion was 1285 and 44 times higher than for cimetidine and famotidine, respectively. The duration of the inhibitory action of IT-066 was significantly longer than that of famotidine and cimetidine. In pylorus ligated rats, IT-066 showed almost 20 times higher potency than omeprazole with intraduodenal administration, and almost the same duration of action as omeprazole with one tenth the dose in oral administration. IT-066 showed a powerful protective effect on various experimental ulcer models. The potency of IT-066 administered subcutaneously was significantly higher compared with that of cimetidine, famotidine and omeprazole. IT-066 given orally also showed a more powerful antiulcer effect than cimetidine and omeprazole, and was comparable with that of famotidine in restraint and water immersion stress and cold-stress plus indometacin induced ulcer models in rats. These results suggest that IT-066 has powerful and long lasting antisecretory and antiulcer effects and is a useful antisecretory drug for treatment of peptic ulcer diseases.     

Synthesis of 7-[p-(methylthio)benzoyl]-5-benzofuranacetic acid

A new method was described for the preparation of 7-[p-(methylthio)benzoyl]-5-benzofuranacetic acid6, which is an analgesic agent. Methyl 5-(2,3-di-hydrobenzofuran)acetate3 was obtained by Friedel-Crafts reaction of 2,3-dihydrobenzofuran with methyl α-chloro-α-(methylthio)actate1 and desulfurization of2. Tifurac6 was synthesized from acylation of 3 with p-(methylthio)benzoyl chloride followed by bromination of4, dehydrohalogenation, and hydrolysis of5.