Disposition of α-[(dimethylamino)methyl]-2-(3-ethyl-5-methyl-4-isoxazolyl)-1H-indole-3- methanol (59–801), a hypoglycaemic agent,in rats,dogs and monkeys

1. The disposition of α-[(dimethylamino)methyl]-2-(3-ethyl-5-methyl-4-isoxazolyl)-1 H-[3-¹⁴C]indole-3-methanol, an oral hypoglycaemic drug, has been studied in the rat, dog and monkey.

2. Oral doses of the drug were almost completely absorbed. The rate of absorption was rapid in the rat but less rapid in dog and monkey. Due to first-pass effect, the absolute bioavailability of the drug was incomplete and ranged from 60–75% in the monkey to 90% in the dog.

3. Intravenous as well as oral doses of the radiolabelled drug were rapidly and extensively distributed to body tissues. In rat, concentrations of radioactivity in all tissues except the brain exceeded, or were similar to, corresponding blood levels. Tissue and blood radioactivity levels were higher in female than in male rats, and increased disproportionately with increasing dose.

4. The drug was partially metabolized before excretion, the extent of metabolism ranging from ca. 50% in the rat to 90% in the monkey. Although only a limited number of animals were used, metabolism appeared to be saturable within the dose range studied in dog and monkey but not in rat. The half-life of unchanged drug was dose-independent in the rat (1.4 h), but tended to increase with increasing dose in the dog (4.1–7.2 h) and monkey (2.1–4.5 h).

5. In all three species, the administered radioactivity was recovered predominantly in urine, although biliary excretion also played an important role in drug elimination. Recovery of dose was essentially complete within 1–2 days.     

Pharmacokinetics and metabolism of oral doses of a 4′-methylthio derivative of propranolol in man

1. The objective of this study was to determine the oral dose pharmacokinetics and metabolism of 4′-methylthiopropranolol (MTP) in man and compare the results with observations for propranolol in previous studies.

2. Three women and five men received single oral doses of MTP, dose range 5-320 mg. Plasma concentration of MTP over time were measured by gas chromatography-mass spectrometry. MTP metabolites in urine were identified by comparative high-performance liquid chromatographic (HPLC) retention times and mass spectrometry with previously characterized reference compounds and quantified by HPLC.

3. The oral clearance of MTP of 1.2–1.41/min for the 80, 160 and 320 mg doses was about one third of the value previously reported for propranolol. The half-life for MTP (3.3–4.1 h) was, however, similar to that of propranolol. In contrast to propranolol, the peak (2.5 h) plasma concentrations of MTP increased linearly with dose (5-320 mg).

4. The oral clearance for MTP was about 2-fold higher in the men than in the women (P<0.01). In addition, the clearance of the (S)-enantiomer was about 30% higher than that of the (R)-enantiomer (P<0.05), which was a reversal of that seen with propranolol.

5. The metabolism of MTP resulted mainly in sulphur oxidation to sulphoxide and sulphone metabolites. These two metabolites accounted for 75% of the MTP dose. This switching from aromatic carbon oxidation for propranolol to sulphur oxidation for MTP is proposed as the basis of the lower oral clearance of MTP.

6. This study also demonstrated higher plasma binding of MTP (unbound fraction 3.7%) than of propranolol (10.5%; P<0.01), a factor probably contributing to decreased tissue distribution of MTP.     

Pharmacokinetics and metabolism of N-[N-[3-(3-hydroxy-4-methoxyphenyl) propyl]-α-aspartyl]-L-phenylalanine 1-methyl ester, monohydrate (advantame) in the rat, dog, and man

The pharmacokinetics and metabolism of advantame were evaluated in rats, dogs, and humans. The oral pharmacokinetic studies using (14)C-advantame showed that advantame undergoes rapid but incomplete absorption, with an oral bioavailability of total radioactivity in the range of 4-23%. Data indicated that absorption was mainly as ANS9801-acid (de-esterified advantame), which was formed in the gastrointestinal tract as a result of the hydrolysis of the methyl ester group of the parent compound. In the dog, plasma ANS9801-acid was present largely in the form of an unidentified conjugate. Advantame (chiefly in the form of metabolites) was mainly excreted in the feces in rats, dogs, and humans (>80% in each species), with urinary excretion representing a minor route. The predominant metabolite of (14)C-advantame detected in the feces and the urine of rats, dogs, and humans was ANS9801-acid, with lower amounts of 3-[3-hydroxy-4-methoxyphenyl]-1-propylamine (termed HU-1) or N-(3-(3-hydroxy-4-methoxy phenyl))propyl-L-aspartic acid (termed HF-1) present, as well as other minor metabolites and areas of indistinct radioactivity. ANS9801-acid, HU-1, and HF-1 were detected and identified in the urine of rats, humans, and dogs, while ANS9801-acid and HF-1 were identified in the feces of humans and dogs. In the feces of rats, in addition to ANS9801-acid, other additional metabolites were detected, including demethylated ANS9801-acid (designated as RF-1) and another unidentified metabolite (designated as RF-2). Overall, the data show generally similar pharmacokinetics of advantame and ANS9801-acid in animals and in humans and close similarity with neotame. Metabolites of advantame that occur in humans are also found in the 2 species utilized in the toxicology studies, and the metabolism studies support the interpretation of safety data from studies conducted in rats and dogs.     

Pharmacokinetics and metabolism of TR-14035, a novel antagonist of α4β1/α4β7 integrin mediated cell adhesion,in rat and dog

The pharmacokinetics and disposition of N-(2,6-dichlorobenzoyl)-4-(2,6-dimethoxyphenyl)-L-phenylalanine (TR-14035), a novel α4β1/α4β7 antagonist, were investigated in the rat and dog. Results indicate extensive clearance of TR-14035 and low oral bioavailability, 17% and 13% in the rat and dog, respectively, at an oral dose of 10?mg/kg. At least 63% of the oral dose was absorbed from the gastrointestinal tract in the rat, and about one-third of the intravenous dose was excreted into bile as unchanged drug in the rat and dog. These data indicate that the oral bioavailability of TR-14035 was limited due to significant first-pass metabolism and biliary excretion in the liver. A species-dependent difference in metabolism was observed. The principal metabolite, O-desmethyl TR-14035, observed in rat, dog and probably human, was further conjugated with sulfate in the rat, but never in dog and human, based on in vitro metabolism and in vivo metabolite profile studies. Urinary excretion was a minor elimination route, but an interesting species difference was recognized. TR-14035 was reabsorbed from the rat renal proximal tubules, and by contrast, secreted into the tubules in the dog, probably via active transport systems.     

Disposition and metabolism of amosulalol hydrochloride,a new combined α- and β-adrenoceptor blocking agent,in rats,dogs and monkeys

1. The disposition and metabolism of amosulalol hydrochloride, a combined α- and β-adrenoceptor blocking agent, were studied in rats, dogs and monkeys.

2. After oral administration of [¹⁴C]amosulalol hydrochloride, the plasma concentration of radioactivity reached a maximum at 05 to 1 h in all species and declined with half-lives of about 2 h in both rats and monkeys, and of about 4 h in dogs. The ratios of unchanged drug to total radioactivity in the rat and dog plasma were 8 and 43% at 05 h after administration, respectively. The radioactivity in the rat tissues was high in the liver, kidney, blood and pancreas after oral administration.

3. Following oral dosage, the urinary excretion of radioactivity was 26-34% of the dose in rats, 45% in dogs and 46% in monkeys in 48 h. The biliary excretion after oral dosage amounted to 66% and 41% in rats and dogs, respectively.

4. Six metabolites were isolated and identified from the urine of rats and dogs. They were derived from one or two of the following pathways: I, hydroxylation of the 2-methyl group of the methylbenzenesulphonamide ring; II, demethylation of the o-methoxy group of the methoxyphenoxy ring; III, hydroxylation at the 4 or 5 position of the methoxy-phenoxy ring; IV, oxidative cleavage of the C—N bond yielding o-methoxyphenoxy acetic acid. Moreover, some metabolites were metabolized to glucuronide or sulphate.     

Absorption, excretion, and metabolism of a potential GABA-A α2/3 receptor modulator in rats

4-Amino-8-(2,5-dimethoxyphenyl)-N-propylcinnoline-3-carboxamide (AZD6280) is a selective GABA-A(α2/3) receptor modulator under development for the treatment of generalized anxiety disorders. Absorption, metabolism, and excretion of [(14)C]-AZD6280 was studied in rats following a single oral (7 mg/kg) or intravenous (i.v., 1 mg/kg) administration of [(14)C]-AZD6280. The results from the bile duct-cannulated study revealed that AZD6280 was well-absorbed in rats. The pharmacokinetic analysis was conducted using unlabelled parent drug that was rapidly absorbed (plasma T(max) ~1 h) and exhibited a mean apparent terminal half-life of ~4.2 h. The overall mean recoveries in the excreta were 98.6% and 100.3% after oral and i.v. administration of [(14)C]-AZD6280, respectively. The major route for elimination of [(14)C]-AZD6280 and its metabolites was through faeces. The radiochromatographic analysis of the excreta demonstrated that AZD6280 underwent extensive biotransformation. A total of 28 metabolites of AZD6280 were detected and profiled in urine, bile, and faeces in this study. The structures of metabolites were elucidated by high-resolution tandem mass spectrometry. Similar metabolite profiles were observed in rats given AZD6280 orally or intravenously.     

The psycho- and neurotropic profiling of novel 3-(N-R,R′-aminomethyl)-2-methyl-1H-quinolin-4-ones in vivo

The article presents the study of psycho- and neurotropic properties of novel 3-(N-R,R′-aminomethyl)-2-methyl-1H-quinolin-4-ones in vivo. The research was carried out using the open field test, elevated plus maze, rotarod test, tail suspension test, passive avoidance test after scopolamine-induced amnesia and acute normobaric hypoxia with hypercapnia. As a result, two promising substances have been found. According to our results 3-[[(4-methoxyphenyl)amino]methyl]-2-methyl-1H-quinolin-4-one in the dose of 10?mg/kg shows a specific sedative effect and a considerable anti-amnesic activity. The most interesting N-[(2-methyl-4-oxo-1H-quinolin-3-yl)methyl]-N-phenylbenzamide (100?mg/kg) combines a potent anti-anxiety action, the anti-amnesic activity and a considerable antihypoxic effect. They are of interest for further profound studies as promising psychoactive compounds.     

Synthesis and antimicrobial evaluation of new 3-alkyl/aryl-2-[((α,α-diphenyl-α-hydroxy)acetyl)hydrazono]-5-methyl-4-thiazolidinones

New 4-thiazolidinone derivatives of benzilic acid (α,α-diphenyl-α-hydroxyacetic acid) have been synthesized and evaluated for antibacterial and antifungal activities. The reaction of 1- (α,α-diphenyl-α-hydroxy)acetyl-4-alkyl/arylthiosemicarbazides with ethyl 2-bromopropionate gave 3-alkyl/aryl-2-[((α,α-diphenyl-α-hydroxy)acetyl)hydrazono]-5-methyl-4-thiazolidinone derivatives. Their antibacterial and antifungal activities were evaluated against S. aureus ATCC 29213, P. aeruginosa ATCC 27853, E. coli ATCC 25922, C. albicans ATCC 10231, C. parapsilosis ATCC 22019, C. krusei ATCC 6258, T. mentagrophytes var. erinacei NCPF 375, M. gypseum NCPF 580 and T. tonsurans NCPF 245. 3e, 3f, 3g and 3h showed the highest antibacterial activity. Particularly 3a and 3e showed the highest antifungal activities against C. parapsilosis ATCC 22019, T. tonsurans NCPF 245 and M. gypseum NCPF 580.     

Association of genes coding for the α-4, α-5, β-2 and β-3 subunits of nicotinic receptors with cigarette smoking and nicotine dependence

We assessed whether smoking behavior was associated with nine polymorphisms in genes coding for the nicotinic receptor subunits α-4 (rs1044394, rs1044396, rs2236196 and rs2273504), α-5 (rs16969968), β-2 (rs2072661 and rs4845378) and β-3 (rs4953 and rs6474413). We conducted an Internet survey and collected saliva by mail for DNA and cotinine analyses, in Switzerland in 2003. We conducted DNA analyses for 277 participants and cotinine analyses for 141 current daily smokers. Cotinine levels were higher in carriers of the CC genotype of CHRNA4 rs1044396 (371 ng/ml) than in those with the CT or TT genotypes (275 ng/ml, p = 0.049), a difference of 0.53 standard deviation units. However, this difference was not robust to correction for multiple testing using Bonferroni adjustment. These 9 polymorphisms were not otherwise associated with smoking behavior and nicotine dependence. There were possible associations between the temperament trait novelty seeking and CHRNA4 rs1044396, CHRNA5 rs16969968 and CHRNB2 rs4845378, but these associations were not robust to correction for multiple testing. We conclude that the analysis of polymorphisms in genes coding for four nicotinic acetylcholine receptor subunits (CHRNA4, CHRNA5, CHRNB2 and CHRNB3) and several smoking-related phenotypes revealed no statistically significant association.     

Evaluation of antidepressant activity of 1-(7-methoxy-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-YL)-cyclohexanol, a β-substituted phenylethylamine in mice

The β-phenylethylamines are known to act as ligands for the trace amine receptors, a novel family of G-protein-coupled receptors. The trace amines are stored and released along with various neurotransmitter agents such as norepinephrine, serotonin, and dopamine and thus work as neuromodulator or neurotransmitter agents. Trace amines are known to play an important role in the pathophysiology of major depression. In our earlier study, we have demonstrated the synthesis of various β-substituted phenylethylamine molecules hypothesized to be effective in various central nervous system disorders. The present study is an attempt to evaluate one of such molecules, 1-(7-methoxy-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-cyclohexanol, in animal models of depression. Various behavioral paradigms of despair such as forced swim and tail-suspension tests were used to assess the antidepressant-like activity. Further, an alteration in the levels of various neurotransmitters (norepinephrine, serotonin, and dopamine) in the mouse brain following 1-(7-methoxy-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-cyclohexanol administration was evaluated. The molecule (4–16 mg/kg., i.p.) dose-dependently inhibited the immobility period in mouse forced swim test, the effect comparable to venlafaxine. The ED50 values of 1-(7-methoxy-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-cyclohexanol and venlafaxine in mouse forced swim test were found to be 5.27 [4.38–6.35] mg/kg., i.p and 4.66 [3.48–6.25] mg/kg., i.p., respectively. Further, 1-(7-methoxy-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-cyclohexanol at 4–16 mg/kg., i.p. reversed the immobility period in mouse tail-suspension test. Additionally, the molecule at 8 mg/kg., i.p. reversed reserpine-induced behavioral despair in mouse forced swim test. When administered simultaneously, it (4 and 8 mg/kg., i.p) enhanced the antidepressant activity of sub-effective doses of imipramine (2 mg/kg., i.p.) or fluoxetine (2 mg/kg., i.p.) in the mouse forced swim test. Neurochemical analysis revealed that the molecule at 8 mg/kg., i.p. increased the levels of norepinephrine (21% increase) without affecting serotonin in the mouse brain. However, at higher dose (16 mg/kg., i.p.), it increased the levels of norepinephrine (13% increase), serotonin (37% increase), and dopamine (42% increase). The molecule enhanced the locomotor activity in mice only at higher doses. The molecule, unlike venlafaxine, which potentiated barbiturate-induced hypnosis, was devoid of any sedative activity. In conclusion, 1-(7-methoxy-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-cyclohexanol, possess antidepressant-like activity in animal models of depression by modulating the neurotransmitter levels in the brain. Such an activity might be due to the modulating action of this novel molecule on trace amine receptors. Such a molecule may be the future drugs of choice for the treatment of major depression.     

4-[[1-[(4-氟苯基)甲基]-1H-2-苯并咪唑基]氨基]-1-哌啶甲酸乙酯的合成

以邻苯二胺为起始原料，经过缩合、氯代、烷基化和取代反应来合成4-[[1-[（4-氟苯基）甲基]-1H-2-苯并咪唑基]氨基]-1-哌啶甲酸乙酯。该合成方法操作简单，总收率达到30．7％。     

Effects of positive modulators of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)-type glutamate receptors in a benzodiazepine-induced deficit of spatial discrimination in mice

Imbalance between GABAergic and glutamatergic neurotransmission has been recently hypothesized to trigger memory decline related either to ageing or to Alzheimer's disease (AD). Thereby, benzodiazepine-induced anterograde amnesia has been construed as a model of hippocampal-related cognitive dysfunctions. Since spatial memory is altered both by ageing and by benzodiazepines such as alprazolam, we investigated the pharmacological sensitivity of alprazolam-induced deficit in a delayed spatial discrimination (SD) task, notably with positive allosteric modulators of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)-type glutamate receptors. We showed that alprazolam (0.1?mg/kg intraperitoneally) induced memory impairments as compared with vehicle-treated mice. The oral administration of modulators of AMPA receptors (IDRA-21: 10?mg/kg; S18986: 3 and 10?mg/kg) reversed the alprazolam-induced deficits. This study is first to show evidence that reference treatments of AD, such as memantine (a NMDA receptor antagonist) at 3?mg/kg per os (po) and donepezil (an acetylcholinesterase inhibitor) at 1?mg/kg po, also reversed the alprazolam-induced amnesia. Given such results, the SD task emerges as a valuable novel task to screen pro-cognitive compounds. Thus, we highlight the efficacy of modulators of AMPA-type glutamate receptors to counteract alprazolam-induced spatial deficits. These results could be viewed alongside the imbalance between excitation and inhibition observed during normal and pathological ageing.     

Absorption, distribution, metabolism, and excretion of [1-¹⁴C]-perfluorohexanoate ([¹⁴C]-PFHx) in rats and mice

The absorption, tissue distribution, elimination, and metabolism of [1-¹⁴C]-PFHx in rats and mice dosed orally at 2 or 100 mg/kg was evaluated following a single dose or after 14 consecutive doses. Absorption was rapid in rats as evidenced by a short time to maximum concentration (C_max) of 30 min in male rats and 15 min in female rats at both the 2 and 100 mg/kg dose level. The plasma elimination half-life was somewhat longer in males (1.5-1.7 h) than in females (0.5-0.7 h). Absorption in the mouse was also rapid with the maximum plasma concentration occurring between 15 and 30 min after dosing. The maximum concentration was not appreciably different between male and female mice (8 μg equiv./g at 2 mg/kg; ∼350 μg equiv./g at 100 mg/kg). The primary route of elimination was via the urine. PFHx was not metabolized in rat or mouse hepatocytes, nor were any metabolites observed after oral dosing in either rodent species. Essentially 100% of the dose was eliminated in urine within 24 h demonstrating that PFHx is readily absorbed and bioavailability approaches 100%, even at a dose as high as 100 mg/kg. The route and extent of elimination was unchanged after 14 days of daily dosing. Tissues were collected at three time points (rat: 0.5, 2, and 24 h; mice: 0.25, 1, and 24 h) after dosing to investigate the tissue clearance kinetics of PFHx following a single dose at 2 or 100 mg/kg. In all tissues except skin, PFHx was not quantifiable 24 h after dosing in both sexes of the two species.     

Crystalline form of a neutrophil elastase inhibitor, 6-methyl-5-(1-methyl-1H-pyrazol-5-yl)-N-{[5-(methylsulfonyl)pyridin-2-yl]methyl}-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide p-toluene sulfonate - is it AZD-9668?: WO-2010094964

This patent application claims a novel crystalline form (Form A) of a tosylate salt of a previously disclosed neutrophil elastase inhibitor. It also claims oral compositions of the salt and a process for the preparation of the crystalline form. The novel form is indicated to show improved physical properties relative to the free base. The claimed compound is evidently one of the elastase inhibitors currently being developed by AstraZeneca.     

Synthesis of 5-chloro-3-[4-(3-diethylaminopropoxy)benzoyl]-2-(4-methoxyphenyl)benzofuran as a β-amyloid aggregation Inhibitor

An efficient synthesis of 5-chloro-3-[4-(3-diethylaminopropoxy)benzoyl]-2-(4-methoxyphenyl)benzofuran (8), a potent beta-amyloid aggregation inhibitor, is described. 5-Chloro-2-(4-methoxyphenyl)benzofuran (3) was obtained by the one-pot synthesis of 4-chlorophenol with omega-(methylsulfinyl)-p-methoxyacetophenone (1) under Pummerer reaction conditions, and it was followed by the desulfurization of the resultant 5-chloro-3-methylthio-2-(4-methoxyphenyl)benzofuran (2e). Acylation of benzofuran 3 with 4-(3-bromopropoxy)benzoyl chloride (6) gave the ketone 7, which was converted into compound 8 by the treatment of diethylamine.     

Synthesis and binding affinities of 5-(3-pyridinyl)- and 5-(3-quinolinyl)-4-azahomoadamantanes to α7 nicotinic acetylcholine receptors

A general synthetic route that can lead to nicotinic ligands bearing a variety of bulky aza-ring systems was developed. This methodology was applied to obtain 5-(3-pyridinyl)- and 5-(3-quinolinyl)-4-azahomoadamantanes 2a, 3a and 2b, 3b. The parent 5-(3-pyridinyl)-4-azahomoadamantane 2a (Ki=5.0 μM) binds with about 100 times lower affinity than (+)−epibatidine 1 (Ki=0.045 μM) to α7 nicotinic acetylcholine receptors (nAChRs). N-methyl substitution of 2a gives compound 3a which has about nine times lower binding affinity. The replacement of pyridinyl with a quinolinyl ring (compounds 2b, 3b) results in a dramatic reduction in potency (Ki>1000 μM).     

Synthesis of 3-(5-bromo-2,3-dimethoxy-phenyl)-[1, 2, 4] oxadiazole analogues and their evaluation as anti-Parkinson′s agents

A series of 3-(5-bromo-2,3-dimethoxy-phenyl)-[1, 2, 4] oxadiazole derivatives was prepared and their evaluation for anti-Parkinson’s activity was measured in vivo using albino rats. The result of the biological activity studies indicated that some of the synthesized compounds have good agonistic activity on the dopamine receptors and a few of them were also found to be free from neurotoxicity. Thus these compounds might be useful ligands for studying the functional role of dopamine receptors in vivo. The high log P value of the compounds indicates that they should easily cross the blood-brain barrier (log P > 2.6).      

Disposition and metabolism of (2S,3S,4R)-N′′-cyano-N-(6-amino-3,4-dihydro-3-hydroxy-2-methyl-2-dimethoxy methyl-2H-benzopyran-4-yl)-N′-benzylguanidine,a novel neuroprotective agent for ischemia-reperfusion damage,in rats

The metabolism and disposition of KR31378 (a benzopyran derivative and a novel neuroprotective agent) were investigated following single oral or intravenous administration of [¹⁴C]-KR31378 to rats. [¹⁴C]-KR31378 was rapidly absorbed after oral dosing with an oral bioavailability of greater than 71%. The maximum plasma concentration and area under the curve of total radioactivity in rat plasma increased proportionally to the administered dose. KR31378 was distributed over all organs and tissues except for brain, eyeball and testis, and declined by first order kinetics up to 24?h after dosing. Excretion of the radioactivity was 29.5% of the dose in the urine and 58.5% in the feces within 2 days after oral administration. Biliary excretion of the radioactivity in bile duct-cannulated rats was about 66.0% for the first 24?h. KR31378 was extensively metabolized by ring hydroxylation, O-demethylation, oxidation and reduction with subsequent N-acetylation and O-glucuronide conjugation. N-acetylated conjugates (M2, M10, M11, M12, M14, and M15) were identified as the predominant metabolites in rats.