Bifunctional [2',6'-dimethyl-L-tyrosine1]endomorphin-2 analogues substituted at position 3 with alkylated phenylalanine derivatives yield potent mixed mu-agonist/delta-antagonist and dual mu-agonist/delta-agonist opioid ligands

Endomorphin-2 (H-Tyr-Pro-Phe-Phe-NH2) and [Dmt1]EM-2 (Dmt = 2',6'-dimethyl-l-tyrosine) analogues, containing alkylated Phe3 derivatives, 2'-monomethyl (2, 2'), 3',5'- and 2',6'-dimethyl (3, 3', and 4', respectively), 2',4',6'-trimethyl (6, 6'), 2'-ethyl-6'-methyl (7, 7'), and 2'-isopropyl-6'-methyl (8, 8') groups or Dmt (5, 5'), had the following characteristics: (i) [Xaa3]EM-2 analogues exhibited improved mu- and delta-opioid receptor affinities. The latter, however, were inconsequential (Kidelta = 491-3451 nM). (ii) [Dmt1,Xaa3]EM-2 analogues enhanced mu- and delta-opioid receptor affinities (Kimu = 0.069-0.32 nM; Kidelta = 1.83-99.8 nM) without kappa-opioid receptor interaction. (iii) There were elevated mu-bioactivity (IC50 = 0.12-14.4 nM) and abolished delta-agonism (IC50 > 10 muM in 2', 3', 4', 5', 6'), although 4' and 6' demonstrated a potent mixed mu-agonism/delta-antagonism (for 4', IC50mu = 0.12 and pA2 = 8.15; for 6', IC50mu = 0.21 nM and pA2 = 9.05) and 7' was a dual mu-agonist/delta-agonist (IC50mu = 0.17 nM; IC50delta = 0.51 nM).     

Synthesis, partition coefficients and antibacterial activity of 3'-phenyl (substituted)-6'-aryl-2' (1H)-cis-3',3'a-dihydrospiro [3-H-indole-3,5'-pyrazolo (3',4'-d)-thiazolo-2-(1H)-ones

Condensation of isatin with primary aryl amines gave a series of Schiff bases (1) which on reaction with thioglycolic acid in 1,4-dioxane afforded the formation of the corresponding 4- thiazolidinones (2). Compound 2 on condensation with substituted benzaldehydes in anhydrous sodium acetate furnished 3-aryl -5'-phenyl (substituted) spiro [3H-indole-3,2'-thiazolidines]-2-(1H), 4'(5'H)-diones (3). The latter (3) on reaction with hydrazine hydrochloride in anhydrous sodium acetate gave 3'-phenyl (substituted) -6'-aryl-2'(1H)-cis-3',3'a-dihydrospiro [3H-indole-3,5'-pyrazolo (3',4'-d)-thiazolo-2-(1H)-ones] (4). The structure has been established on the basis of spectral data. The partition coefficient for n-octanol/water solvent system and in vitro antibacterial activity of the 2'(1H)-cis-3',3'a-dihydrospiro [3H-indole-3,5'-pyrazolo (3',4'-d)-thiazolo-2-(1H)-one] derivatives have been evaluated.     

TSAO analogues. Stereospecific synthesis and anti-HIV-1 activity of 1-[2',5'-bis-O-(tert-butyldimethylsilyl)-beta-D-ribofuranosyl]-3'-spiro -5'- (4'-amino-1',2'-oxathiole 2',2'-dioxide) pyrimidine and pyrimidine-modified nucleosides.

Several analogues of a new lead for anti-HIV-1 agents [1-[2',5'-bis-O-(tert-butyldimethylsilyl)-beta-D-ribofuranosyl]-thymine] -3'-spiro-5'-(4'-amino-1',2'-oxathiole 2',2'-dioxide) (TSAO) modified at positions N-3, O-4 and C-5 of the thymine moiety, have been prepared and evaluated as inhibitors of HIV-1 replication. A new stereoselective synthetic procedure is described. Reaction of 1,2-di-O-acetyl-5-O-benzoyl-3-C-cyano-3-O-mesyl-D-ribofuranose with pyrimidine bases, followed by treatment with Cs2CO3 afforded stereoselectively, beta-D-ribofuranosyl-3'-spiro nucleosides. 2',5'-O-Deacylation and subsequent treatment with tert-butyldimethylsilyl chloride gave the TSAO derivatives. Only those analogues having a tBDMSi group at both the C-5' and C-2' positions of the ribose moiety showed potent anti-HIV-1 activity. The activity ranged from 0.060 microM to 1.0 microM. Introduction of an alkyl or alkenyl function at N-3 of the thymine ring markedly decreased cytotoxicity without affecting the antiviral activity. While markedly active against HIV-1, the TSAO derivatives had no activity against HIV-2 or SIV. They represent the first example of nucleoside analogues with an intact ribose moiety that discriminate between HIV-1 and other retroviruses.     

Purpactins, new inhibitors of acyl-CoA:cholesterol acyltransferase produced by Penicillium purpurogenum. II. Structure elucidation of purpactins A, B and C

The structure of purpactins, novel acyl-CoA:cholesterol acyltransferase (ACAT) inhibitors, was determined by spectroscopic analyses. Purpactin A was deduced to be 3-1'-acetoxy-11-hydroxy-4-methoxy-9-methyl-3'-methylbutyl-5H, 7H-dibenzo[b,g]-1,5-dioxocin-5-one, purpactin B was 5-1'-acetoxy-6'-hydroxymethyl-4-methoxy-4'-methyl-3'-methylbutyl-spiro [benzofuran-2,1'-cyclohexa-3',5'-diene]-2',3(2H)-dione and purpactin C was 5-1'-acetoxy-6'-formyl-4-methoxy-4'-methyl-3'-methylbutyl-spiro [benzofuran-2,1'-cyclohexa-3',5'-diene]-2',3(2H)-dione. Purpactin A was attributed to 1'-O-acetylpenicillide.     

1,5-benzodiazepine derivatives of 3-arylsydnones: synthesis and antimicrobial activity of 3-aryl-4-[2'-aryl-2',4',6',7'-tetrahydro-(1'H)-1',5'-benzodiazepine-4' -yl]sydnones

The alpha-beta-unsaturated ketones of 3-arylsydnones (Ia-y) were treated with 1,2-phenylenediamine to obtain the 3-aryl-4-[2'-aryl- 2',4',6',7'-tetrahydro-(1'H)-1',5'-benzodiazepine-4'-yl]sydnones (IIa-y) in high yield. All the new compounds synthesised were screened for antibacterial and antifungal activities.     

Synthesis and monoamine transporter binding properties of 3beta-(3',4'-disubstituted phenyl)tropane-2beta-carboxylic acid methyl esters

3beta-(3'-Methyl-4'-chlorophenyl)tropane-2-carboxylic acid methyl ester (3b, RTI-112) is a 3-phenyltropane analogue that has high affinity for both the dopamine and serotonin transporters (DAT and 5-HTT, respectively). Compound 3b shows significant reduction of cocaine self-administration in rhesus monkeys, yet fails to maintain robust drug self-administration. PET studies revealed that unlike more DAT selective analogues such as GBR 12 909 and 3-(4-chlorophenyl)tropane-2-carboxylic acid phenyl ester (RTI-113), 3b shows no detectible DAT occupancy when dosed at its ED(50) for reduction of cocaine self-administration. In contrast, it highly occupies the 5-HTT at this dose. In this study, we report the synthesis and monoamine transporter binding potency of several new 3-(3',4'-disubstituted phenyl)tropane-2-carboxylic acid methyl esters (3c-k), which have binding properties very similar to 3b. With the exception of the 3',4'-dimethyl analogue 3k, all of the compounds possess subnanomolar IC(50) and K(i) values at the DAT and 5-HTT, respectively. The 3'-chloro-4'-bromo analogue 3e (IC(50) = 0.12 nM) and the 3'-bromo-4'-iodo analogue 3i (K(i) = 0.14 nM) are the most potent analogues at the DAT and 5-HTT, respectively. These compounds will be useful to further characterize the highly interesting behavioral profile of 3b.     

A novel nitration product formed during the reaction of peroxynitrite with 2',3',5'-tri-O-acetyl-7,8-dihydro-8-oxoguanosine: N-nitro-N'-[1-(2,3,5-tri-O-acetyl-beta-D-erythro-pentofuranosyl)- 2, 4-dioxoimidazolidin-5-ylidene]guanidine

A novel nitration product, formed during the reaction of peroxynitrite with 2',3',5'-tri-O-acetyl-7,8-dihydro-8-oxoguanosine, has been characterized using a combination of UV/vis, CD, and NMR spectroscopy and mass spectrometry. This compound has been identified as N-nitro-N'-[1-(2,3, 5-tri-O-acetyl-beta-D-erythro-pentofuranosyl)-2, 4-dioxoimidazolidin-5-ylidene]guanidine (IV). Upon base hydrolysis, IV releases nitroguanidine (IVa) and an intermediate, 1-(2,3, 5-tri-O-acetyl-beta-D-erythro-pentofuranosyl)-5-iminoimidazolidine -2, 4-dione (IVb). This intermediate is ultimately hydrolyzed to the stable 3-(2,3,5-tri-O-acetyl-beta-D-erythro-pentofuranosyl)oxaluric acid (IVc). IV can be reduced by sodium borohydride to a pair of stable diastereomers (IV(red)()). The formation of this product is rationalized in terms of initial oxidation of 2',3', 5'-tri-O-acetyl-7,8-dihydro-8-oxoguanosine to a quinonoid diimine intermediate, 3. Nucleophilic attack at C5 of 3 by peroxynitrite leads to formation of a C5-oxyl radical species, 5, which then undergoes a series of rearrangements to yield an ylidene radical, 7. Combination of this radical species with nitrogen dioxide results in the formation of product IV.     

Divergent effects of the purinoceptor antagonists suramin and pyridoxal-5'-phosphate-6-(2'-naphthylazo-6'-nitro-4',8'-disulfonate) (PPNDS) on alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors

Suramin is a large naphthyl-polysulfonate compound that inhibits an array of receptors and enzymes, and it has also been reported to block currents mediated by glutamate receptors. This study shows that suramin and several structurally related compounds [8,8'-[carbonylbis(imino-3,1-phenylenecarbonylamino)]bis-(1,3,5-naphthalenetrisulfonic acid), 6Na (NF023), 8,8'-(carbonylbis(imino-4,1-phenylenecarbonylimino-4,1-phenylenecarbonylimino))bis-1,3,5-naphthalenetrisulfonic acid, Na (NF279), and 4,4',4',4'-[carbonyl-bis[imino-5,1,3-benzenetriyl-bis-(carbonylimino)]]tetrakis-benzene-1,3-disulfonic acid, 8Na (NF449)] reduce binding of [3H]alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) and [3H]fluorowillardiine to rat brain membranes and homomeric GluR1-4 receptors, with IC50 values in the range of 5 to 180 microM. Inhibition often was less than complete at saturating drug concentrations and thus seems to be noncompetitive in nature. Pyridoxal-5'-phosphate-6-(2'-naphthylazo-6'-nitro-4',8'-disulfonate) (PPNDS) is a potent antagonist of purinoceptors that shares some structural elements with suramin yet is smaller than the latter. PPNDS also had potent effects on AMPA receptors (EC50 value of 4 microM) but of a kind not seen with the other compounds in that it increased binding affinity for radioagonists severalfold. In addition, PPNDS slowed association and dissociation rates more than 10 times. In physiological experiments with GluR2 receptors, PPNDS at 50 microM reduced the peak current by 30 to 50% but had only small effects on other waveform aspects such desensitization and steady-state currents. This pattern of effects differentiates PPNDS from other compounds such as thiocyanate and up-modulators, which increase agonist binding by enhancing desensitization or slowing deactivation, respectively. Receptor model simulations indicate that most effects can be accounted for by assuming that PPNDS slows agonist binding/unbinding and stabilizes the bound-closed state of the receptor. By extension, suramin is proposed to stabilize the unbound state and thereby to reduce affinity for agonists. These drugs thus act through a novel type of noncompetitive antagonism.     

Guanosine analogues. Synthesis of nucleosides of certain 3-substituted 6-aminopyrazolo[3,4-d]pyrimidin-4(5H)-ones as potential immunotherapeutic agents

Several guanosine analogues were synthesized in the pyrazolo[3,4-d]pyrimidine ring system with various substituents at the 3-position. The new analogues prepared here include the CH3 (2-amino-3-methyl-1-beta-D-ribofuranosylpyrazolo[3,4-d]pyrimidin-4 (5H)-one, 13a), the phenyl (2-amino-3-phenyl-1-beta-D-ribofuranosylpyrazolo[3,4-d]pyrimidin-4 (5H)-one, 13b), and the NH2 (3,6-diamino-1-beta-D-ribofuranosylpyrazolo[3,4-d]pyrimidin-4(5H)- one, 17) substituted derivatives. These new agents, as well as several other 3-substituted derivatives including H, Br, OCH3, COOH, and oxo, were evaluated for their ability to potentiate certain murine immune functions relative to the known active agent 5-amino-3-beta-D-ribofuranosylthiazolo[4,5-d]pyrimidine-2,7(3H,6H) -dione (4, 7-thia-8-oxoguanosine). The biological evaluation included the (1) ex vivo determination of increased natural killer cell function and (2) in vivo antiviral protection against a lethal challenge of Semliki Forest virus. The 3-unsubstituted (5a) and the 3-bromo (5c) derivatives were found to be the most active immunopotentiators in this series.     

Synthesis and benzodiazepine receptor affinity of derivatives of the new tricyclic heteroaromatic system pyrido[3',2':5,6]thiopyrano[4,3-c]pyridazin-3(2H,5H)-one

Derivatives 7-13 of a new tricyclic heteroaromatic system, pyrido[3',2':5,6]thiopyrano[4,3-c]pyridazin-3(2H,5H)-one, were prepared as potential ligands at the benzodiazepine receptor, in view of their structural analogy with potent ligands such as the pyrazoloquinolines of the CGS series II, and especially with the benzothiopyrano[4,3-c]pyridazinones VI. They were obtained starting from the versatile ketones 2,3-dihydrothiopyrano[2,3-b]pyridin-4(4H)-one 1 and the corresponding 7-methyl derivative 2, via condensation with glyoxylic acid, and reaction of the intermediate acid mixtures with hydrazine or substituted phenylhydrazines. When evaluated for their binding affinity at the benzo diazepine receptor in bovine cortical membranes, the target compounds 8-13 displayed an affinity in the micromolar/submicromolar order. A hypothesis is presented to rationalize these results.     

含(1',2'-二-O-环亚己基二氧乙基)的二氧代氮杂茂并[3',4'-d]异噁唑啉衍生物对Cdc25A和CD45的抑制作用

在三乙胺的作用下,以α-氯代-1',2'-二-O-环亚己基二氧乙基甲醛肟产生的氧化腈为偶极体,N-芳基-马来酰亚胺为亲偶极体,通过1,3-偶极环加成反应合成了15个3-(1',2'-二-O-环亚己基二氧乙基)-5-芳基-3a,6a-二氢-4,6-二氧代氮杂茂并[3',4'-d]异噁唑啉衍生物(3a～3o),利用1H NMR、IR和元素分析对其结构进行了表征,并进行了初步活性筛选,部分化合物显示了不同程度的抗癌、抗炎及免疫性疾病活性。初步体外抗癌活性结果表明,当样品浓度为20μg.mL 1时,化合物3e、3h、3j和3l对Cdc25A磷酸酯酶的抑制率分别为60.6%、58.6%、51.4%和98.4%,其中3l的抑制率最高,甚至当样品浓度为5μg.mL 1时,化合物3l的抑制率仍为86.97%,值得进一步研究。此外,初步体外白细胞共同抗原活性结果表明,当样品浓度为20μmol.mL 1时,化合物3e、3l和3n对CD45蛋白酪氨酸磷酸酶A的抑制率分别为57.7%、74.4%和77.3%。在此基础上,初步讨论了该类化合物的构效关系。     

Fluorine-containing heterocycles: synthesis and some reactions of new 3-amino-2-functionalized-6-(2'-thienyl)-4-trifluoromethylthieno [2,3-b]pyridines

3-Cyano-6-(2'-thienyl)-4-trifluoromethylpyridine-2(1H)-thione (2) was prepared and reacted with chloroacetone or phenacyl bromide to yield the 2-acetyl or benzoyl-3-amino-6-(2'-thienyl)-4-trifluoromethylthieno[2,3-b]pyridines (3a, b). In contrast, the reaction of 2 with chloroacetamide or its N-aryl derivatives gave the corresponding 2-carbamoylmethyl thiopyridines 4a-c. Upon treatment of these educts with K2CO3 or C2H5ONa in ethanol, they underwent intramolecular Thorpe-Ziegler cyclization to afford 3-amino-2-carbamoyl-6-(2'-thienyl)-4-trifluoromethyl-thieno[2,3-b]pyridine (5a) and its N-aryl analogs 5b, c. Compounds 5a-c underwent some reactions to yield new pyrido[3',2':4,5]thieno[3,2-d]pyrimidines and pyrido[3',2':4,5]thieno[3,2-d][1,2,3] triazines.     

Synthesis and antifungal activity of novel pyrano[2',3':4,5]thiazolo[2,3-b]quinazolines, pyrido[2',3':4,5]thiazolo[2,3-b]quinazolines and pyrazolo[2',3':4,5]thiazolo[2,3-b]quinazolines

The starting materials thiazolo[2,3-b]quinazolines (5a,b) were obtained in one pot synthesis by treating octahydroquinazoline (2) with chloroacetic acid and aromatic aldehydes. Thiazoloquinazoline (5) was reacted with CH2(CN)2/piperidine and CH2(CN)2/NaOH (CH3OH), to furnish pyrano[2',3':4,5]thiazolo[2,3-b]quinazolines (6a,b) and pyrido[2',3':4,5]thiazolo[2,3-b]quinazoline (7), respectively. Refluxing of 5a with NH2CSNH2/KOH and hydrazines in ethanol furnished the corresponding, [1,3]thiazino[4'5':4,5]thiazolo[2,3-b]quinazoline (10) and pyrazolo[3',4':4,5]thiazolo[2,3-b]quinazolines (11a,b), respectively. Antifungal activity was shown for some of the synthesized compounds.     

Structural determinants of AMPA agonist activity in analogues of 2-amino-3-(3-carboxy-5-methyl-4-isoxazolyl)propionic acid: synthesis and pharmacology

We have previously shown that the 2-amino-3-(3-hydroxy-5-methyl-4-isoxazolyl)propionic acid (AMPA) receptor agonist, 2-amino-3-(3-carboxy-5-methyl-4-isoxazolyl)propionic acid (ACPA, 2), binds to AMPA receptors in a manner different from that of AMPA (1) itself and that 2, in contrast to 1, also binds to kainic acid receptor sites. To elucidate the structural requirements for selective activation of the site/conformation of AMPA receptors recognized by 2, a number of isosteric analogues of 2 have now been synthesized and pharmacologically characterized. The compound 2-amino-3-(5-carboxy-3-methoxy-4-isoxazolyl)propionic acid (3a) (IC(50) = 0.11 microM; EC(50) = 1.2 microM), which is a regioisostere of 2 with a methoxy group substituted for the methyl group, was approximately equipotent with 2 (IC(50) = 0.020 microM; EC(50) = 1.0 microM) as an inhibitor of [(3)H]AMPA binding and as an AMPA agonist, respectively, whereas the corresponding 3-ethoxy analogue 3b (IC(50) = 1.0 microM; EC(50) = 4.8 microM) was slightly weaker. The analogues 3c-e, containing C3 alkoxy groups, were an order of magnitude weaker than 3b, whereas the additional steric bulk of the alkoxy groups of 3f-i or the presence of an acidic hydroxyl group at the 3-position of the isoxazole ring of 3j prevented interaction with AMPA receptor sites. The 2-amino-3-(2-alkyl-5-carboxy-3-oxo-4-isoxazolyl)propionic acids 4a,b, i, which are regioisosteric analogues of 3a,b,i, showed negligible interaction with AMPA recognition sites. Similarly, replacement of the carboxyl group of 3b by isosteric tetrazolyl or 1,2,4-triazolyl groups to give 5 and 6, respectively, or conversion of 3b into analogue 7, in which the diaminosquaric acid group has been bioisosterically substituted for the alpha-aminocarboxylic acid unit, provided compounds completely devoid of effect at AMPA receptors. In contrast to the parent compound ACPA (2) (IC(50) = 6.3 microM), none of the analogues described showed detectable inhibitory effect on [(3)H]kainic acid receptor binding.     

Novel pyrazolopyrimidopyridazinones with potent and selective phosphodiesterase 5 (PDE5) inhibitory activity as potential agents for treatment of erectile dysfunction

Pyrazolo[1',5':1,6]pyrimido[4,5-d]pyridazin-4(3H)-ones and their analogues, potentially useful for the treatment of erectile dysfunction, were synthesized and evaluated as inhibitors of phosphodiesterase 5 (PDE5). Several compounds showed IC50 values in the low nanomolar range, and in particular, compound 5r, displaying high potency toward PDE5 (IC50 = 8.3 nM) and high selectivity versus PDE6 (240-fold) appeared to be a very promising new lead both in comparison with the potent but not selective sildenafil and in comparison with some analogues previously reported by us. SAR studies in this triheterocyclic scaffold led us to conclude that the best arranged groups are a methyl in position 1, a benzyl in position 3, a phenyl in position 9, and a linear four-carbon chain in position 6.     

Synthesis and receptor affinities of some conformationally restricted analogues of the dopamine D1 selective ligand (5R)-8-chloro-2,3,4,5-tetrahydro-3-methyl-5-phenyl- 1H-3-benzazepin-7-ol

The synthesis of a structurally novel series of 6,6a,7,8,9,13b-hexahydro-5H-benzo[d]naphtho[2,1-b]azepines (2), conformationally restricted analogues of the dopamine D1 antagonist (5R)-8-chloro-2,3,4,5-tetrahydro-3-methyl-5-phenyl-1H-3-benzazepin -7-ol (SCH 23390, 1c), is described. Affinity for D1 receptors was determined by competition for rat striatal binding sites labeled by [3H]SCH 23390; affinity for D2 receptors was similarly determined by competition experiments using [3H]spiperone. Compounds in this series having the B/C-trans ring junction (2b and related analogues), where the D ring is unequivocally fixed in an equatorial orientation, possess considerably more D1 receptor affinity and selectivity vs the D2 receptor than the conformationally mobile cis stereoisomers (2a), thus leading to the conclusion that axial substituents at the 4- or 5-positions of the benzazepine nucleus are detrimental to D1 receptor affinity. Resolution and X-ray analysis demonstrated that D1 receptor affinity was preferentially associated with the (-)-6aS,13bR enantiomer of 2b.     

Novel sites for phenylalkylamines: characterisation of a sodium-sensitive drug receptor with (-)-[3H]emopamil.

(-)-Emopamil ((S)-emopamil, (2S)-2-isopropyl-5-(methylphenethylamino)- 2-phenylvaleronitrile hydrochloride) is a Ca(2+)-antagonistic phenylalkylamine which also blocks serotonin (5-HT2) receptors and has antiischemic properties. The (-)-[3H]emopamil tissue distribution profile of specific binding is in striking contrast to that observed for (+)-[3H]PN 200-110 or (-)-[3H]desmethoxyverapamil: (-)-[3H]emopamil labels membrane fractions from guinea-pig liver much greater than adrenal gland greater than kidney approximately lung approximately ductus deferens approximately brain approximately skeletal muscle. Binding to liver membrane was saturable (KD = 12.8 nM, Bmax = 35 pmol/mg of protein), stereoselective, reversible (K-1 = 0.22 min-1 at 25 degrees C) and inhibited by tetraethylammonium (IC50: 1.8 mM) greater than Li+ (IC50: 12.5 mM) approximately Na+ (IC50: 13.6 mM) and [NH4+] (IC50: 79.3 mM) but not by Rb+, Cs+ or K+. The high-affinity liver membrane binding sites have a pharmacological profile that is distinct from the phenylalkylamine receptor domain of the voltage-dependent L-type Ca2+ channel. Similar sites exist in brain and other tissues, albeit with a lower density. Amiodarone, butoprozine and amiloride derivatives bind with high affinity whereas 1,4-dihydropyridines do not interact at all. It is suggested that the novel phenylalkylamine site is linked to a sodium-dependent carrier or transport system.     

Main metabolites of 1-(2-chloroethyl)-3-[1'-(5'-p-nitrobenzoyl-2',3'-isopropylidene)-alpha, beta-D-ribofuranosyl]-1-nitrosourea and 1-(2-chloroethyl)-3-(2',3', 4'-tri-O-acetyl-alpha, beta-D-ribopyranosyl)-1-nitrosourea in rats

The metabolism of two glycosylnitrosoureas, 1-(2-chloroethyl)-3-[1'-(5'-p-nitrobenzoyl-2',3'-isopropylidene)-alpha, beta-D-ribofuranosyl]-1-nitrosourea (RFCNU) and 1-(2-chloroethyl)-3-(2',3',4'-tri-O-acetyl-alpha, beta-D-ribopyranosyl)-1-nitrosourea (RPCNU), has been investigated in the rat. With the label on the carboxyl moiety of RFCNU, we have shown that hydrolysis of the 4-nitrobenzoyl ester occurred to a large extent in vivo; 4-nitrobenzoic acid and its glucuronide were the major urinary metabolites. Two other minor metabolites and their glucuronides were identified as 4-aminobenzoic acid and 4-acetamidobenzoic acid. With the label on the chloroethyl moieties of RFCNU and RPCNU, we have shown that chloroethanol was a major degradation product of this alkylating part of the molecule. The concentration of chloroethanol in plasma vs. time has been determined. In urine, four metabolites derived from alkylated glutathione, namely thiodiacetic acid and its sulfoxide, N-acetylcarboxymethylcysteine, and N-acetylhydroxyethylcysteine, have been identified.     

4-(2-[2-(2(R)-methylpyrrolidin-1-yl)ethyl]benzofuran-5-yl)benzonitrile and related 2-aminoethylbenzofuran H3 receptor antagonists potently enhance cognition and attention

H(3) receptor antagonists based on a 2-aminoethylbenzofuran skeleton have been discovered, which are potent in vitro at human and rat H(3) receptors, with K(i) values of 0.1-5.8 nM. Analogues were discovered with potent (0.01-1 mg/kg) cognition and attention enhancing properties in animal models. One compound in particular, 4-(2-[2-(2(R)-methylpyrrolidin-1-yl)ethyl]benzofuran-5-yl)benzonitrile (ABT-239), combined potent and selective H(3) receptor antagonism and excellent pharmacokinetic and metabolic properties across species, with full efficacy in two behavioral models: a five-trial inhibitory avoidance acquisition model in rat pups at 0.1 mg/kg and a social recognition memory model in adult rats at 0.01 mg/kg. Furthermore, this compound did not stimulate locomotor activity and showed high selectivity for the induction of behavioral efficacy versus central nervous system based side effects. The potency and selectivity of this compound and of analogues from this class support the potential of H(3) receptor antagonists for the treatment of cognitive dysfunction.