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M Jarman

Publications and source records attributed to M Jarman.

At least 91 records · Page 5Linked to original sources
PubMed1987

Analogues of 3-ethyl-3-(4-pyridyl)piperidine-2,6-dione as selective inhibitors of aromatase: derivatives with variable 1-alkyl and 3-alkyl substituents.

3-Ethyl-3-(4-pyridyl)piperidine-2,6-dione (1) is a strong competitive inhibitor of human placental aromatase (Ki = 1.1 microM; testosterone as substrate) that, unlike the structurally related aromatase inhibitor aminoglutethimide (2), is not also an inhibitor of the cholesterol side-chain cleavage enzyme desmolase. An improved synthesis of 1 is described, which was readily adapted to the preparation of homologues in a series of 3-alkyl-3-(4-pyridyl)-piperidine-2,6-diones (6-13). Alkylation of 1 afforded a second series, comprising 1-alkyl-3-ethyl-3-(4-pyridyl)-piperidine-2,6-diones (14-23). Inhibitory activity toward aromatase was maximal in both series for the octyl derivatives. Respective Ki values for the competitive inhibition exerted by the 3-octyl (12) and the 1-octyl (21) analogues with testosterone as substrate were 0.09 and 0.12 microM. The compounds 1, 2, 12, and 21 differed in their relative potencies as inhibitors of the aromatization of testosterone and androstenedione. Respective Ki values were as follows: for 1, 1.1 and 14 microM (ratio 12.7); for 2, 0.6 and 1.8 microM (3); for 12, 0.09 and 0.20 microM (2.2); and for 21, 0.12 and 0.48 microM (4).

Alkylation↗
PubMed1986

Pyridoglutethimide [3-ethyl-3-(4-pyridyl)-piperidine-2,6-dione], an analogue of aminoglutethimide. Metabolism and pharmacokinetics.

Pyridoglutethimide [3-ethyl-3-(4-pyridyl)piperidine-2,6-dione] has been developed as an analogue of aminoglutethimide [3-(4-aminophenyl)-3-ethyl-piperidine-2,6-dione] possessing specific aromatase activity with potency comparable to aminoglutethimide. This study investigates the pharmacokinetics of pyridoglutethimide in the rat and the rabbit: the plasma half-life is 6 hr in the rat and 16.4 hr in the rabbit. The sole metabolite found in urine (rat) and plasma (rat and rabbit) is pyridoglutethimide N-oxide.

Aminoglutethimide↗
PubMed1986

Factors responsible for the formation of different N-alkylated porphyrins in rat liver microsomal systems exposed to norethindrone. The role of 3 alpha-hydroxysteroid dehydrogenase.

Incubation of rat liver microsomes with norethindrone and a NADPH-generating system leads to the formation of one N-alkylated porphyrin (green pigment, GP1). Administration of this steroid to male rats in vivo results in the formation of three more-polar green pigments (GP2, 3 and 4). A cytosolic protein (green-pigment converting protein) has been purified from rat liver that, when added to liver microsomal mixtures containing norethindrone (0.03 mM) and a NADPH-generating system, results in the formation of all four green pigments (GP1, 2, 3 and 4). Field-desorption mass spectrometry of the purified green pigments gave protonated molecules, [M + H]+, at m/z 905 for GP1, m/z 909 for GP2, m/z 925 for GP3 and 4. The Mr of the purified cytosolic protein on SDS/polyacrylamide-gel electrophoresis or gel filtration was 37000. Polyacrylamide-gel isoelectric focusing gave a pI value of 5.9. Antibodies raised in rabbits against this protein, after preincubation with rat liver cytosol, subsequently prevented the formation of the more-polar norethindrone-induced green pigments (GP2, 3 and 4). The purified protein in the presence of either NADH or NADPH catalysed the reduction of delta 4-ring-reduced norethindrone, 5 alpha-oestran-17 alpha-ethynyl-17 beta-ol-3-one and, with the appropriate cofactor, the oxidation and reduction of steroids lacking the ethynyl function, e.g. androsterone or dihydrotestosterone. Indomethacin inhibited the reduction of dihydrotestosterone by this protein with an I50 (concn. causing 50% inhibition) value of 4.9 microM. From its physical and enzymic properties it is concluded that green-pigment converting protein is the same as 3 alpha-hydroxysteroid dehydrogenase (EC 1.1.1.50).

3-Hydroxysteroid Dehydrogenases↗
PubMed1986

Metabolism of 4-hydroxyandrost-4-ene-3,17-dione by rat hepatocytes.

4-[14C]HAD was rapidly metabolized (99% after 5 min) by hepatocytes from phenobarbital-treated rats. An array of phase I metabolites was formed, variously involving one and two reductions, hydroxylation, hydration and hydroxylation plus one or two reductions. Some of the metabolites were identified by synthesis and others tentatively by mass spectrometry. After 10 min, approximately 30% of the original radioactivity was present in HAD glucuronide and, after 15 min, approximately 60% was present in the total glucuronide fraction which contained several components. Only one of the phase I metabolites (2-hydroxy-HAD) exhibited significant aromatase inhibitory activity (45% of that of HAD).

Androstenedione↗
PubMed1986

Metabolism of the aromatase inhibitor 4-hydroxyandrostenedione in vivo. Identification of the glucuronide as a major urinary metabolite in patients and biliary metabolite in the rat.

4-Hydroxyandrost-4-ene-3,17-dione (HAD) is a potent and selective inhibitor of the enzyme complex aromatase, both in vitro and in vivo. The glucuronide is a major metabolite in the urine of patients and in the bile of rats given HAD and it was identified by chemical ionization-MS of the permethylated derivative. HAD glucuronide was quantified by first converting it enzymically into HAD, then determining HAD by capillary column GC-MS of the perfluorotolyl derivative using 4-hydroxyandrost-2,4-diene-3,17-dione as internal standard.

Androstenedione↗
PubMed1986

The metabolism of N-nitrosomorpholine by rat liver microsomes and its oxidation by the Fenton system.

The metabolism of N-nitrosomorpholine by rat liver microsomes gave acetaldehyde, formaldehyde, glyoxal and N-nitroso-2-hydroxymorpholine. Oxidation of N-nitrosomorpholine by Fenton's reagent gave acetaldehyde, glycolaldehyde, glyoxal, (2-hydroxyethoxy)acetaldehyde and N-nitroso-2-hydroxymorpholine. N-Nitroso-3-hydroxymorpholine was synthesised. In water the new compound gave mainly acetaldehyde, with glycolaldehyde, (2-hydroxyethoxy)acetaldehyde and glyoxal. These observations indicated the probability of 3-hydroxylation in the biological and chemical oxidations. N-Nitroso-3-morpholone behaved similarly in water to the 3-hydroxy compound, and gave mainly acetaldehyde, with glycollic acid, (2-hydroxyethoxy)acetic acid and glyoxal. N-Nitroso-3-morpholone and N-nitroso-3-hydroxymorpholine reacted with 3,4-dichlorobenzenethiol. The action of light or alkali on N-nitrosomorpholine gave glyoxal and labile glyoxal-yielding compounds.

Acetaldehyde↗
PubMed1986

The testis temperature of anaesthetized quail.

The temperatures of the left testis, and of the adjacent viscera, of 11 anaesthetized quail were measured. The testes averaged 0.6 degrees C cooler than the surrounding viscera and 1.3 degrees C cooler than the fight muscle. We suggest that endothermic reactions are the cause of the testicular temperature being below that of its immediate surroundings.

Anesthesia, General↗
PubMed1986

Effect of omega-trifluorination on the microsomal metabolism of ethyl and pent-1-yl p-nitrophenyl ether.

p-Nitrophenyl pent-1-yl ether was metabolized (65-70%) in the presence of liver microsomes from phenobarbital-treated rats to give the 4-(major), 3-(minor), and 2-hydroxypent-1-yl (minor) derivatives which were characterized by g.l.c.-mass spectrometry; O-dealkylation (reflecting 1-hydroxylation) and 5-hydroxylation did not occur to a significant extent. 5,5,5-Trifluorination of the pent-1-yl group markedly reduced the extent of metabolism (to approximately 10%). p-Nitrophenyl 2,2,2-trifluoroethyl ether was virtually completely resistant to microsomal metabolism under conditions where the ethyl analogue was extensively O-dealkylated.

Animals↗
PubMed1986

Analogues of tamoxifen: the role of the basic side-chain. Applications of a whole-cell oestrogen-receptor binding assay to N-oxides and quaternary salts.

Derivatives of tamoxifen (1) and 4-hydroxy-2-methyltamoxifen (2) in which the basic side chain has been modified by N-oxidation or by quaternization have been investigated with respect to the effects on affinity for the oestrogen receptor and on cytostatic activity towards the MCF-7 cell line in vitro. In addition to the conventional cytosol assay for receptor binding affinity (RBA) a recently developed whole-cell assay was employed. N-oxidation (e.g. 2----3) produced no significant alteration in RBA value either in cytosol or in whole cells, nor in activity towards the MCF-7 line. Quaternization with methyl iodide (1----4, 2----6) or ethyl bromide (1----5, 2----7b: the cis isomer 7a also formed) did not alter receptor binding in the cytosol assay but almost abolished binding in the whole cell and cytostatic activity. The whole-cell RBA values for 2 (0.45) and 3 (0.5) were lower than those for 4-hydroxytamoxifen (2.9), suggested to be due to the lower oestrogenicity of the 2-methyl derivatives since activity against MCF-7 cells was unimpaired. The even lower values of whole-cell RBA (0.01-0.02) for the quaternary ethyl bromide derivatives 7a and 7b were ascribed to poor penetration into the cell since these compounds had minimal cytostatic activity.

Animals↗
PubMed1986

Pharmacokinetics of the thymidylate synthase inhibitor N10-propargyl-5,8-dideazafolic acid (CB3717) in the mouse.

The tissue distribution, excretion, and metabolism of the thymidylate synthase inhibitor N10-propargyl-5,8-dideazafolic acid (CB3717) have been investigated in the mouse. Following 100 mg/kg of 2-14C-CB3717 ip, levels of radioactivity in the brain, testes, muscle, heart, and lung equilibrated slowly with those in the plasma and were no longer significantly lower 5 hours (lung) and 12 hours (brain, testes, muscle, and heart) after administration. In contrast, concentrations of 14C in the liver and kidney were markedly higher than those in the plasma at all time points studied (1.3 hours-23 days). High-performance liquid chromatographic (HPLC) analysis of livers removed 5 hours after drug administration and kidneys excised 24 hours after treatment indicated that, at these time points, greater than 50% of the radioactivity was in the form of unchanged CB3717. Furthermore, HPLC analysis of plasma removed over the period 0.5-6 hours demonstrated that all of the 14C could be accounted for as CB3717. Although the accumulation and retention of radioactivity in the liver and kidney were also apparent following 20 and 200 mg/kg of 14C-CB3717, the effect was less marked at the lower dose, thereby suggesting dose-dependent pharmacokinetics. In excretion studies (0-48 hours), the major route of elimination was found to be via the feces, with 46% of the 14C recovered; 26% of the dose was recovered as unchanged CB3717. Radioactivity excreted in the urine accounted for 20% of the administered 14C, while CB3717 eliminated via this route represented 15% of the dose. In addition to CB3717, a metabolite was detected in the feces which comprised 8% of the dose administered. The metabolite was shown to be 4-(N-((2-amino-4-hydroxy-6-quinazolinyl)methyl)prop-2-ynylamino) benzoic acid (CB3751) by HPLC and mass spectrometry. The formation of CB3751 could be catalyzed in vitro by the contents of the cecum and prevented in vivo by antibiotic pretreatment and is therefore considered to be the result of bacterial metabolism. CB3717 binds extensively to plasma proteins (92%; concentration range, 25-250 microM). These studies have shown that CB3717 does not apparently undergo extensive host metabolism in vivo, and therefore the biological properties of this novel antimetabolite are probably a function of the parent compound. In addition, the accumulation of CB3717 in the liver and kidney may be related to the hepatotoxic and nephrotoxic effects of this drug.

Animals↗
PubMed1985

Hydroxy derivatives of tamoxifen.

In the exploration of the structural features that affect the RBA (binding affinity for the estrogen receptor of rat uterus relative to that of estradiol) in the tamoxifen [trans-(Z)-1-[4-[2-(dimethylamino)ethoxy]phenyl ]-1,2-diphenyl-1-butene] series, several derivatives variously substituted in the 1-phenyl group have been synthesized. [In the tamoxifen series, the descriptors E and Z, which define the configuration of the geometrical isomers and depend on the location and nature of substituents in the aromatic moieties and the ethyl group, may vary, although the relative configuration (cis or trans) does not. In order to avoid confusion the terms cis and trans will be used in this paper to refer to the relative positions of the 4-[2-(dimethylamino)ethoxy]phenyl and ethyl (or hydroxyethyl, hydroxypropyl, or bromo) substituents attached to the ethene moiety.] The final stage of each synthesis involved acid-catalyzed dehydration of a tertiary alcohol, and, in contrast to the known 3- and 4-hydroxy derivatives which were obtained as near-equimolar cis,trans mixtures, only the trans forms of the 2-hydroxy, 2-methyl, 2,4-dihydroxy, and 4-hydroxy-2-methyl derivatives were obtained. Also, in contrast to the trans forms of the 3- and 4-hydroxy derivatives, which are readily equilibrated to cis,trans mixtures, the trans 2-hydroxy derivative could not be isomerized. Tamoxifen and 2-methyltamoxifen had similar RBA's (approximately 1% of that of E2), but that of 2-hydroxytamoxifen was much lower (0.1%). Introduction of a second hydroxyl group (2,4-dihydroxy derivative) enhanced the RBA, and for the 4-hydroxy-2-methyl derivative, the RBA and growth inhibitory activity against the MCF-7 mammary tumor cell line in vitro were high and comparable to those of 4-hydroxytamoxifen, a metabolite of the parent drug. Tamoxifen derivatives hydroxylated at positions 3 or 4 of the 1-butene moiety and the 5-hydroxy-1-pentene analogue were also synthesized, but they had very low RBA values.

Binding, Competitive↗
PubMed1985

Analogues of aminoglutethimide: selective inhibition of aromatase.

In exploring further the structural features that influence the relative efficacy of analogues of aminoglutethimide [1, 3-(4-aminophenyl)-3-ethylpiperidine-2,6-dione] as inhibitors of the cholesterol side-chain cleavage enzyme system desmolase and the estrogen forming system aromatase, analogues have been synthesized in which the aminophenyl substituent is replaced by pyridyl or substituted pyridyl. The 4-pyridyl analogue 5 [3-ethyl-3-(4-pyridyl)-piperidine-2,6-dione] is a strong competitive inhibitor of aromatase (Ki = 1.1 microM; value for 1, 0.60 microM), which exhibits a type II difference spectrum (Ks = 0.28 microM; value for 1, 0.13 microM) but is noninhibitory toward desmolase. The 2- and 3-pyridyl analogues (3 and 4) inhibit neither enzyme system. 1-Amino-3-ethyl-3-phenylpiperidine-2,6-dione (2) is a strong and selective inhibitor of desmolase but the 4-pyridyl analogue 10 [1-amino-3-ethyl-3-(4-pyridyl)-piperidine-2,6-dione] is a weak inhibitor of desmolase and aromatase. Analogues of 5 having a less basic aromatic substituent, namely, the N-oxide 11 and the 2,3,5,6-tetrafluoro derivative 13, were also prepared. The latter is a weak inhibitor of aromatase and the former inhibits neither enzyme system.

Aminoglutethimide↗
PubMed1985

Metabolism of aminoglutethimide in humans: quantification and clinical relevance of induced metabolism.

Hydroxylaminoglutethimide [3-ethyl-3-(4-hydroxylaminophenyl)piperidine-2,6-dione] (HxAG), aminoglutethimide [3-(4-aminophenyl)-3-ethylpiperidine-2,6-dione] (AG) and N-acetyl-aminoglutethimide (N-AcAG) have been quantified by high performance liquid chromatography using m-aminoglutethimide (metaAG) as the internal standard in serial 24 h urine collections from a patient on chronic AG therapy without steroid supplementation. HxAG is the product of a major AG-induced metabolic pathway since the ratio [HxAG]/[AG] rises with time. In contrast the ratio [N-AcAG]/[AG] decreases with time. A rapid, simple colorimetric assay has been used to quantify HxAG in urine from both male and female patients receiving a range of doses of AG and to show that induced metabolism is a general phenomenon even at low doses (125 mg twice daily). AG therapy is known to alter the metabolic rate and plasma half-life of a number of coadministered compounds including dexamethasone and warfarin. Clinicians should remain alerted to this phenomenon.

Aminoglutethimide↗
PubMed1984

Metabolism of 1,1,1,2,2-pentafluorohexane and 1,1-difluorocyclohexane by rat liver microsomes in vitro.

Metabolism of 1,1,1,2,2-pentafluorohexane with liver microsomes from phenobarbital-treated rats gave only one metabolite, namely, the 5-hydroxy derivative. Under similar conditions 1,1-difluorocyclohexane was metabolized to give mainly the 3- and 4-hydroxy derivatives in the ratio 1: approximately 5.5. The structures of these metabolites were established by chemical ionization (CI) and/or electron impact (EI) mass spectrometry and confirmed by synthesis in the case of 1,1-difluorocyclohexan-4-ol. Oxidation of 1,1-difluorocyclohexane with lead tetrakis(trifluoroacetate) also gave, inter alia, the 3- and 4-hydroxy derivatives. In saturated hydrocarbons complete replacement of hydrogen by fluorine at one particular carbon will not only block microsomal hydroxylation thereat but will also inhibit hydroxylation at neighbouring hydrogen-bearing carbons, (alpha almost completely, beta markedly, gamma slightly).

Animals↗
PubMed1983

Metabolism of aminoglutethimide in humans: identification of hydroxylaminoglutethimide as an induced metabolite.

Hydroxylaminoglutethimide (3-ethyl-3-(4-hydroxylaminophenyl)-2,6-piperidinedione) has been identified as a novel metabolite of aminoglutethimide (3-(4-aminophenyl)-3-ethyl-2,6-piperidinedione) in the urine of patients treated chronically with this drug. The metabolite was isolated by reverse-phase thin-layer chromatography, and characterized by comparison of its mass spectrum and chromatographic properties with those of the synthetic compound. Hydroxylaminoglutethimide is unstable; it is readily oxidized to nitrosoglutethimide and disproportionates in the mass spectrometer into this compound and aminoglutethimide. In none of four patients studied was the metabolite detected in the urine after the first dose of the drug. In one patient it appeared after the second dose and in two more within seven to eight days suggesting that its formation is drug-induced, and that it may be the metabolite responsible for the diminished half-life of aminoglutethimide during chronic therapy. The profile of metabolites from one patient, examined by high-performance liquid chromatography after the first dose and again after six weeks of therapy afforded evidence that the formation of hydroxylaminoglutethimide was at the expense of a major metabolite N-acetylaminoglutethimide. Hydroxylaminoglutethimide was not an induced metabolite in the rat.

Aminoglutethimide↗
PubMed1983

Analogues of aminoglutethimide: selective inhibition of cholesterol side-chain cleavage.

In our probing of the structural features responsible for the inhibitory activity of aminoglutethimide [1, 3-(4-aminophenyl)-3-ethylpiperidine-2,6-dione] toward the cholesterol side-chain cleavage enzyme system desmolase and the estrogen-forming system aromatase, targets in the action of 1 against hormone-dependent mammary tumors, analogues in several categories have been synthesized and evaluated. Of the known monoamino derivatives, the meta derivative [2, 3-(3-aminophenyl)-3-ethylpiperidine-2,6-dione] was as inhibitory toward desmolase as 1, and the N-amino analogue [4, 1-amino-3-ethyl-3-phenylpiperidine-2,6-dione] was three times as inhibitory (respective Ki values of 1, 2, and 4 are 14, 13, and 4.6 microM), but 2 was a weak inhibitor and 4 was a noninhibitor of aromatase. Another amino analogue [5, 5-amino-3-ethyl-3-phenylpiperidine-2,6-dione] inhibited neither enzyme system. Reaction of glutethimide (11) with hydrazine and thermal cyclization of the resulting amide hydrazide (15) afforded an improved synthesis of 4. Analogues having a second amino substituent, either at C-5 (10) or at N-1 (14) of the piperidine-2,6-dione residue, were less inhibitory than was 1 toward desmolase and aromatase. Among analogues having little or no inhibitory activity were hydroxy derivatives of 1 and 2, namely, 3-(4-amino-3-hydroxyphenyl)-3-ethylpiperidine-2,6-dione (20) and the 3-amino-4-hydroxy analogue (21).

Aminoglutethimide↗