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PubMed1996

Indole inhibitors of human nonpancreatic secretory phospholipase A2. 1. Indole-3-acetamides.

Phospholipases (PLAs) produce rate-limiting precursors in the biosynthesis of various types of biologically active lipids involved in inflammatory processes. Increased levels of human nonpancreatic secretory phospholipase A2 (hnps-PLA2) have been detected in several pathological conditions. An inhibitor of this enzyme could have therapeutic utility. A broad screening program was carried out to identify chemical structures which could inhibit hnps-PLA2. One of the lead compounds generated by the screening program was 5-methoxy-2-methyl-1-(phenylmethyl)-1H-indole-3-acetic acid (13a). We describe the syntheses, structure--activity relationships, and pharmacological activities of a series of indole-3-acetamides and related compounds derived from this lead. This SAR was undertaken with the aid of X-ray crystal structures of complexes between the inhibitors and hnps-PLA2 which were of great value in directing the SAR.

Animals↗
PubMed1998

Efficacious, orally bioavailable thrombin inhibitors based on 3-aminopyridinone or 3-aminopyrazinone acetamide peptidomimetic templates.

We have addressed the key deficiency of noncovalent pyridinone acetamide thrombin inhibitor L-374,087 (1), namely, its modest half-lives in animals, by making a chemically stable 3-alkylaminopyrazinone bioisostere for its 3-sulfonylaminopyridinone core. Compound 3 (L-375,378), the closest aminopyrazinone analogue of 1, has comparable selectivity and slightly decreased efficacy but significantly improved pharmacokinetics in rats, dogs, and monkeys to 1. We have developed an efficient and versatile synthesis of 3, and this compound has been chosen for further preclinical and clinical development.

Aminopyridines↗
PubMed1999

New N-(pyridin-4-yl)-(indol-3-yl)acetamides and propanamides as antiallergic agents.

A series of new N-(pyridin-4-yl)-(indol-3-yl)alkylamides 44-84 has been prepared in the search of novel antiallergic compounds. Synthesis of the desired ethyl (2-methyindol-3-yl)acetates 1-4 was achieved by indolization under Fischer conditions; Japp-Klingemann method followed by 2-decarboxylation afforded the ethyl (indol-3-yl)alkanoates 17-25. Amidification was successfully carried out by condensation of the corresponding acids or their N-aryl(methyl) derivatives with 4-aminopyridine promoted by 2-chloro-1-methylpyridinium iodide. Efforts to improve the antiallergic potency of the title series by variation of the indole substituents (R1, R2, R) and the length of the alkanoic chain (n = 1, 2, 3) led to the selection of N-(pyridin-4-yl)-[1-(4-fluorobenzyl)indol-3-yl]acetamide 45, out of 41 compounds. This amide was 406-fold more potent than astemizole in the ovalbumin-induced histamine release assay, using guinea pig peritoneal mast cells, with an IC50 = 0.016 microM. Its inhibitory activity in IL-4 production test from Th-2 cells was identical to that of the reference histamine antagonist (IC50 = 8.0 microM) and twice higher in IL-5 assay: IC50 = 1.5 and 3.3 microM, respectively. In vivo antiallergic activity evaluation confirmed efficiency of 45 in sensitized guinea pig late phase eosinophilia inhibition, after parenteral and oral administration at 5 and 30 mg/kg, respectively. Its efficiency in inhibition of microvascular permeability was assessed in two rhinitis models; ovalbumin and capsaicin-induced rhinorrhea could be prevented after topical application of submicromolar concentrations of 45 (IC50 = 0.25 and 0.30 microM); and it also exerted significant inhibitory effect in the first test after iv and oral administration, with ID50 = 0.005 and 0.46 mg/kg.

Acetylcholine↗
PubMed2001

The C-N rotation barrier of the lithium enolate of acetamide: an ab initio and density functional theory investigation.

Semiempirical (PM3), ab initio (HF/6-31+G(d) and MP2/6-31+G(d)), and density functional (pBP/DN) calculations are used to investigate the rotation barrier of the carbon-nitrogen bond in a simple enolate anion: lithium acetamide, 1. For comparison, the amidate anion 2, vinylamine 3, and a simulated dimer 4 were also calculated. In all systems, the barrier to rotation was found to be less than 10 kcal x mol(-1) in agreement with experiment. The correlated calculations show the barrier to be lowest for the anion 2. The results show conjugation effects in 1 and 2 comparable to that in vinylamine 3 and imply that polarization effects are more important than charge transfer in amine conjugation.

Journal Article↗
PubMedDate not supplied

Oxidations of the carcinogen N-hydroxy-N-(2-fluorenyl)acetamide by enzymatically or chemically generated oxidants of chloride and bromide.

The oxidations of the carcinogen N-hydroxy-N-(2-fluorenyl)acetamide (N-OH-2-FAA) via one-electron (1e-) oxidation to equimolar 2-nitrosofluorene (2-NOF) and N-acetoxy-2-FAA and via oxidative cleavage to 2-NOF by chemically and myeloperoxidase (MPO)/H2O2 generated oxidants of Cl- and/or Br- were investigated. 2-NOF was determined spectrophotometrically in the reaction mixtures and by HPLC of their extracts; N-acetoxy-2-FAA was determined by HPLC. In the presence of individual or mixed halides at their physiologic concentrations (0.1 M Cl- and/or 0.1 mM Br-) and pH 4-6, MPO/H2O2-catalyzed oxidation of N-OH-2-FAA to 2-NOF via oxidative cleavage was much greater than 1e- oxidation. At the respective pH optima, oxidation was much more rapid with Br- and Br- + Cl- than with Cl-. HOBr or HOCl + Br- oxidized N-OH-2-FAA more rapidly than HOCl, also chiefly via oxidative cleavage. This suggested that, in the presence of MPO/H2O2 + Cl- + Br-, oxidation was due to HOBr from HOCl oxidation of Br- and/or oxidation of Br- by MPO/H2O2. In the presence of taurine (1 or 10 mM), a scavenger of hypohalous acids, MPO/H2O2 catalysis of oxidative cleavage was unaffected with Br-, prevented with Cl-, and partially prevented with Cl- + Br-. These results were linked to N-halotaurine formation since it was found that N-bromotaurine, but not N-chlorotaurine, oxidized N-OH-2-FAA chiefly to 2-NOF. With time N-chlorotaurine and N-bromotaurine appeared to undergo a pH-dependent halide exchange with Br- and Cl-, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)

Bromides↗
PubMedDate not supplied

Activation of the carcinogen N-hydroxy-N-(2-fluorenyl)benzamide via chemical and enzymatic oxidations. Comparison to oxidations of the structural analogue N-hydroxy-N-(2-fluorenyl)acetamide.

Chemical or enzymatic oxidations of the carcinogen N-hydroxy-N-(2- fluorenyl)benzamide (N-OH-2-FBA) were investigated under the conditions facilitating one-electron oxidation or oxidative cleavage of N-hydroxy-N-(2-fluorenyl)acetamide (N-OH-2-FAA). HPLC methods were developed for separation and quantitation of the above hydroxamic acids and their respective oxidation products. To identify the products of oxidation of N-OH-2-FBA, N-(benzoyloxy)-2-FBA (N-BzO-2-FBA) was synthesized and shown to undergo ortho rearrangement to 1- and 3-BzO-2-FBA. Oxidation of N-OH-2-FBA (4.88 mM) with alkaline K3Fe(CN)6 in benzene was complete and yielded equimolar amounts of 2-nitrosofluorene (2-NOF) and the ester (chiefly N-BzO-2-FBA), indicative of one-electron oxidation to nitroxyl free radical which undergoes bimolecular dismutation. However, one-electron oxidation of N-OH-2-FBA (30 or 10 microM) by horseradish peroxidase/H2O2 at pH 7 or myeloperoxidase/H2O2 at pH 6.5 yielded only approximately 10% as much product as N-OH-2-FAA (30 microM). The addition of 0.1 mM Br- +/- 0.1 M Cl- at pH 4 to 6.5 increased 2-NOF formation in MPO/H2O2-catalyzed oxidations. Simulations of these oxidations with HOCl/Cl- or HOBr/Br- showed that the latter was more efficient, converting N-OH-2-FAA almost completely and less than or equal to 62% of N-OH-2-FBA to 2-NOF. The amounts of the ester (N- and o-BzO-2-FBA), which by itself did not contribute to 2-NOF formation or significant substrate regeneration, indicated that approximately 10% of 2-NOF originated from one-electron oxidation.(ABSTRACT TRUNCATED AT 250 WORDS)

Biotransformation↗
PubMed1999

Stereoselective pharmacokinetics and pharmacodynamics of propylisopropyl acetamide, a CNS-active chiral amide analog of valproic acid.

PURPOSE: The purpose of this study was to evaluate there existed stereoselective effects in the pharmacokinetics, anticonvulsant activity, microsomal epoxide hydrolase (mEH) inhibition, and teratogenicity of the two enantiomers of propylisopropyl acetamide (PID), a CNS-active chiral amide analogue of valproic acid. METHODS: Racemic PID, as well as the individual enantiomers, were intravenously administered to six dogs in order to investigate the stereoselectivity in their pharmacokinetics. Anticonvulsant activity was evaluated in mice (ip) and rats (oral), mEH inhibition studies were performed in human liver microsomes, and teratogenicity was evaluated in an inbred susceptible mice strain. RESULTS: Following intravenous administration to dogs of the individual enantiomers, (R)-PID had significantly lower clearance and longer half-life than (S)-PID, however, the volumes of distribution were similar. In contrast, following intravenous administration of racemic PID, both enantiomers had similar pharmacokinetic parameters. In rats (oral), (R)-PID had a significantly lower ED50 in the maximal electroshock seizure test than (S)-PID; 16 and 25 mg/kg, respectively. PID enantiomers were non-teratogenic and did not demonstrate stereoselective mEH inhibition. CONCLUSIONS: (R)-PID demonstrated better anticonvulsant activity, lower clearance and a longer half-life compared to (S)-PID. When racemic PID was administered, the clearance of (S)-PID was significantly reduced, reflecting an enantiomer-enantiomer interaction.

Allylisopropylacetamide↗
PubMed2003

Characterization of the anticonvulsant profile and enantioselective pharmacokinetics of the chiral valproylamide propylisopropyl acetamide in rodents.

1. Propylisopropyl acetamide (PID) is a new chiral amide derivative of valproic acid. The purpose of this study was to evaluate the anticonvulsant activity of PID in rodent models of partial, secondarily generalized and sound-induced generalized seizures which focus on different methods of seizure induction, both acute stimuli, and following short-term plastic changes as a result of kindling, and to assess enantioselectivity and enantiomer-enantiomer interactions in the pharmacokinetics and pharmacodynamics of racemic PID and its pure enantiomers in rodents. 2. Anticonvulsant activity of (S)-PID, (R)-PID and racemic PID was evaluated in the 6 Hz psychomotor seizure model in mice, in the hippocampal kindled rat, and in the Frings audiogenic seizure susceptible mouse. The pharmacokinetics of (S)-PID and (R)-PID was studied in mice and rats. 3. In mice (S)-PID, (R)-PID and racemic PID were effective in preventing the 6 Hz seizures with (R)-PID being significantly (P < 0.05) more potent (ED(50) values 11 mg kg(-1), 46 mg kg(-1) and 57 mg kg(-1) at stimulation intensities of 22, 32 and 44 mA, respectively) than (S)-PID (ED(50) values 20 mg kg(-1), 73 mg kg(-1) and 81 mg kg(-1) at stimulation intensities of 22, 32 and 44 mA, respectively). (S)-PID, (R)-PID and racemic PID also blocked generalized seizures in the Frings mice (ED(50) values 16 mg kg(-1), 20 mg kg(-1) and 19 mg kg(-1) respectively). 4. In the hippocampal kindled rat a dose of 40 mg kg(-1) of (R)- and (S)-PID prevented the secondarily generalized seizure, whereas racemic PID also blocked the expression of partial seizures following an i.p. dose of 40 mg kg(-1). Racemic PID also significantly increased the seizure threshold in this model. 5. Mechanistic studies showed that PID did not affect voltage-sensitive sodium channels or kainate-, GABA- or NMDA- evoked currents. 6. The pharmacokinetics of PID was enantioselective following i.p. administration of individual enantiomers to mice, with (R)-PID having lower clearance and longer half-life than (S)-PID. In rats and mice, no enantioselectivity in the pharmacokinetics of PID was observed following administration of the racemate, which may be due to enantiomer-enantiomer interaction. 7. This study demonstrated that PID has both enantioselective pharmacokinetics and pharmacodynamics. The better anticonvulsant potency of (R)-PID in comparison to (S)-PID may be due to its more favorable pharmacokinetic profile. The enhanced efficacy of the racemate over the individual enantiomers in the kindled rat may be explained by a pharmacokinetic enantiomer-enantiomer interaction in rats. This study also showed the importance of studying the pharmacokinetics and pharmacodynamics of chiral drugs following administration of the individual enantiomers as well as the racemic mixture.

Allylisopropylacetamide↗
PubMed2006

Unprecedented formation of an acetamidate-bridged dinuclear platinum(II) terpyridyl complex-correlation of luminescence properties with the crystal forms and dimerization studies in solution.

An [corrected] acetamidate-bridged dinuclear platinum(ii) terpyridyl complex has been isolated in two crystal forms, a red form and a dark form, with different luminescence properties; electronic absorption, emission and (1)H NMR studies revealed the presence of a dimerization process in the solution state.

Amides↗
PubMed2003

Developmental outcome of levetiracetam, its major metabolite in humans, 2-pyrrolidinone N-butyric acid, and its enantiomer (R)-alpha-ethyl-oxo-pyrrolidine acetamide in a mouse model of teratogenicity.

PURPOSE: The purpose of this study was to test the teratogenic potential of the antiepileptic drug (AED) levetiracetam (LEV), its major metabolite in humans, 2-pyrrolidone-N-butyric acid (PBA), and enantiomer, (R)-alpha-ethyl-oxo-pyrrolidine acetamide (REV), in a well-established mouse model. METHODS: All compounds were administered by intraperitoneal injections once daily to SWV/Fnn mice on gestational days 8-1/2 to 12-1/2. LEV was administered at doses of 600, 1,200, and 2,000 mg/kg/day, piracetam (PIR) and PBA, at 600 and 1,200 mg/kg/day, and REV, at 600 mg/kg/day. On gestational day 18(1/2), fetuses were examined for gross external malformations and prepared for skeletal analysis by using Alizarin Red S staining. RESULTS: No significant gross external malformations were observed in any of the study groups. Fetal weights were significantly reduced in most study groups. Resorption rates were significantly increased only in the 2,000-mg/kg/day LEV group. The overall incidence of skeletal abnormalities and specifically of hypoplastic phalanges was significantly increased in both PBA treatments and in the intermediate 1,200-mg/kg/day LEV group. In contrast to that in humans, 24-h urinary excretion analysis in mice showed that 65-100% of the LEV doses were excreted unchanged, whereas only 4% was excreted as the metabolite PBA. CONCLUSIONS: Results of this study demonstrate that both LEV and its major metabolite in humans, PBA, do not induce major structural malformations in developing SWV/Fnn embryos and suggest that they provide a margin of reproductive safety for the pregnant epileptic population when compared with other AEDs tested in this mouse model.

Animals↗
PubMed1975

[Pilot study of 2-pyrrolidon-acetamid (generic name: piracetam) (author's transl)].

Ten chronic schizophrenics were tested by clinical observations, psychological tests (FPI, LEV, d 2) and ratings with the Wittenborn-Psychiatric-Ratings-Scales (WPRS) before and after taking 2-pyrrolidon-acetamid. The improvement of obstructive, apathy, withdrawal and affective flatness in seven patients justify a double-blind psychometric evaluation concerning the effect of Piracetam on the schizophrenic deficiency states.

Adult↗
PubMed2001

Endothelin receptor antagonist activity of (R)-(-)-2-(benzo[1,3]dioxol-5-yl)-N-(4-isopropylphenylsulfonyl)-2-(6-methyl- 2-propylpyridin-3-yloxy)acetamide hydrochloride (PABSA) in rat aortic smooth muscle cells and isolated rat thoracic aorta.

Antagonist activities of (R)-(-)-2-(benzo[1,3]dioxol-5-yl)-N-(4-isopropylphenylsulfonyl)-2-(6-methyl- 2-propylpyridin-3-yloxy) acetamide hydrochloride (CAS 188710-94-3, PABSA), a novel endothelin (ET) receptor antagonist, for ETA and ETB receptors were evaluated using rat aortic smooth muscle A7r5 cells and isolated rat thoracic aorta. PABSA concentration-dependently inhibited the ET-1-induced increase in intracellular calcium concentration ([Ca2+]i) mediated via ETA receptors in A7r5 cells with an IC50 of 0.17 nmol/l. PABSA antagonized the ETA receptor-mediated contraction induced by ET-1 in endothelium-denuded rat aorta with a Kb of 0.74 nmol/l. The potency of PABSA in inhibiting ETA receptor-mediated vasocontraction was approximately 40- and 100-fold greater than those of BQ-123, a selective ETA antagonist, and bosentan, a mixed ETA/ETB receptor antagonist, respectively. ETB receptor-mediated endothelium-dependent vasorelaxation induced by ET-3 in the aorta was also antagonized by PABSA, with a Kb of 9.8 nmol/l. In contrast, PABSA affected neither the vasocontraction induced by KCl or norepinephrine nor the vasorelaxation induced by acetylcholine or prostaglandin I2 in the aorta. These results suggest that PABSA is a highly potent and selective ETA receptor antagonist.

Animals↗
PubMed1984

Metabolic activation of the carcinogen N-[4-(5-nitro-2-furyl)-2-thiazolyl]acetamide by prostaglandin H synthase.

It has been demonstrated that N-[4-(5-nitro-2-furyl)-2-thiazolyl]acetamide (NFTA), when fed with the diet, causes transitional carcinomas in rats. An important step in the mechanism of NFTA-induced carcinogenesis is endogenous metabolic activation to an ultimate carcinogen. We have proposed that the enzyme complex prostaglandin H synthase (PHS) is involved in the activation of certain renal and urinary tract carcinogens. This proposal was assessed by examining the activation of the 5-nitrofuran renal carcinogen NFTA and its deacetylated analogue 2-amino-4-(5-nitro-2-furyl)thiazole (ANFT) by PHS. Ram seminal vesicular and rabbit renal inner medullary microsomes were used as a source of PHS. Both NFTA and ANFT were activated by PHS to bind microsomal protein. Both microsomal preparations activated ANFT to bind DNA. However, only ram seminal vesicular microsomes activated NFTA to bind DNA. The rate of ANFT binding to macromolecules was considerably greater than NFTA with both microsomal preparations. Although activated ANFT was shown to bind several different homopolynucleotides, a preference for binding polyguanylic acid was demonstrated. Glutathione inhibition of carcinogen binding to macromolecules was shown to be due to the formation of a thioether conjugate. Deacetylation of NFTA was demonstrated in both tissues with deacetylation significantly exceeding acetylation of ANFT to NFTA in the kidney. Thus, renal PHS activation of both NFTA and ANFT was demonstrated with the rate of ANFT activation being considerably greater than NFTA. The conversion of NFTA to ANFT by intact tissue suggests that ANFT may contribute to NFTA renal carcinogenesis.

Acetylation↗
PubMed1984

Effect of lead acetate on N-(4'-fluoro-4-biphenyl)acetamide-induced renal carcinogenesis in the rat.

This study assessed the effect of lead acetate (Pb) on N-(4'-fluoro-4-biphenyl)acetamide (FBPA)-induced renal carcinogenesis. A quantitative investigation was performed to determine the effects of Pb on the numerical density (Nv) and percent volume (%V) of FBPA-induced renal tubular hyperplasia and microscopic nodules. A secondary goal was to evaluate, on a quantitative basis, the role of these putative premalignant lesions in the development of renal carcinoma. Additionally, by quantifying the number per unit area of karyomegalic cells, their relationship to the neoplastic process was examined. Generally, Pb was found to accelerate the onset and development of all renal lesions. Karyocytomegaly did not serve as an indicator of the degree of carcinogenicity of any of the treatment regimens.

Adenocarcinoma↗
PubMed1976

Adenocarcinoma of the kidney. I. Ultrastructure of renal adenocarcinomas induced in rats by N-(4'-fluoro-4-biphenylyl)acetamide.

The ultrastructure of tumors induced in kidneys of F344 rats by the carcinogen N-(4'-fluoro-4-biphenylyl)acetamide appeared similar in many aspects to that described in humans and other animal models. The neoplastic cells exhibited microvilli resembling brush border and other adaptations of the cell membrane. Tumor lobules were surrounded by basement membrane-like material, which also extended into the tumor mass between individual cells. The ultrastructure appeared to reflect a proximal tubular origin of these lesions.

Adenocarcinoma↗
PubMed1976

Adenocarcinoma of the kidney. II. Enzyme histochemistry of renal adenocarcinomas induced in rats by N-(4'-fluoro-4-biphenylyl)acetamide.

Activities of a broad spectrum of enzymes were studied histochemically in renal adenocarcinomas induced in young male F344 rats by chronic dietary administration of the carcinogen N(4'-fluoro-4-biphenylyl)acetamide. Enzymes included were: dehydrogenases of glucose-6-phosphate, lactate, succinate, malate, and alpha-glycerophosphate; peroxidase (catalase); glucose-6-phosphatase; alkaline and acid phosphatase; Mg2+ ATPase; 5'-nucleotidase; and aminopeptidase. Levels of enzyme activity were estimated visually and scored from 0 (not detectable) to a maximum of 5 (intense). Comparison of estimated activity for each enzyme was made between small neoplastic nodules (stage III tumors) and large adenocarcinomas (stage IV tumors) and between tumors and portions of normal proximal tubules in parenchyma of kidneys from untreated control rats. The results, which revealed nearly identical levels of activity for most enzymes in both stages III and IV tumors, suggested similar metabolic and biologic behavior of these lesions. However, when data for tumors were compared with data for normal proximal tubules, striking differences were observed consistent with: 1) a marked shift of energy metabolism from oxidative to glycolytic production of ATP, with a corresponding reduction in mitochondrial respiration; and 2) simplification of plasma membrane specializations that were possibly associated with a reduction or loss of transport function. These findings were compared with other histochemical, biochemical, and ultrastructural studies of renal adenocarcinomas in rats and man.

Adenocarcinoma↗
PubMed1980

Adenocarcinoma of the kidney. III. Histogenesis of renal adenocarcinomas induced in rats by N-(4'-fluoro-4-biphenylyl)acetamide.

The histogenesis of renal adenocarcinoma induced in F344 rats by the carcinogen N-(4'-fluoro-4-biphenylyl)acetamide (FBPA) was described in order to clarify the site of origin of this neoplasm within the nephron. FBPA was added to the diet up to 48 weeks, and the animals were killed at intervals from 4 to 52 weeks after initiation of the carcinogenic diet. As seen by light microscopy, tumors appeared to arise from the pars recta of the proximal tubule in a series of stages progressing from focal hyperplasia with dysplasia to development of small, then large, neoplastic nodules composed of moderately basophilic, closely packed tumor cells arranged in individual aggregates or lobules surrounded by basement membrane-like material. Karyomegaly, cystic lesions, foam cell lesions, interstitial fibrosis, and casts also accompanied tumorigenesis in this animal model.

Adenocarcinoma↗