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

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

Synthesis of new pyrido[4',3':4,5]thieno[2,3-d]-1,2,4-triazolo[3,4-c]pyrimidines and a 5,6-dihydro-1,2,4-triazolo[4",3":1',2']pyrido[4',3':4,5]thieno [2,3-d]-pyrimidine ring system

A series of substituted pyrido[4',3':4,5]thieno[2,3-d]-1,2,4-triazolo[3,4-c]pyrimidines 4-6, 8, pyrido[4',3':4,5]thieno[2,3-d]-1,2,4-triazolo[3,4-c]pyrimidines 11-13 and 5,6-dihydro-1,2,4-triazolo[4",3":1',2']pyrido[4',3':4,5]thieno[2,3-d] pyrimidines 16-19 have been synthesized from 3, 10 and 15 through the reaction with orthoesters and carbon disulphide, respectively.     

Beta 1- and beta 2-adrenoceptor antagonist activities of ICI-215001, a putative beta 3-adrenoceptor agonist.

1. The present study was undertaken to characterize the beta 3-adrenoceptor agonist activity of ICI-215001 and to determine whether it exhibits additional activities on beta 1- and beta 2-adrenoceptors in isolated spontaneously beating atrium, trachea and ileum of guinea-pig. 2. In guinea-pig atrium, isoprenaline, a non-selective beta-adrenoceptor agonist, caused concentration-dependent, positive chronotropic effects that were inhibited by atenolol, a selective beta 1-antagonist. ICI-215001 also competitively antagonized the increase in heart rate caused by isoprenaline. 3. ICI-215001 exhibited low intrinsic activity at increasing the beating rate of atrium and no activity on resting or induced tone of tracheal strips. 4. In strips of guinea-pig trachea, contracted submaximally with carbachol, isoprenaline, caused concentration-dependent relaxations. Both ICI-118551, a selective beta 2-adrenoceptor antagonist, and ICI-215001 competitively inhibited the relaxations caused by isoprenaline. 5. In isolated strips of guinea-pig ileum longitudinal smooth muscle contracted with histamine, isoprenaline and ICI-215001 caused relaxations which were inhibited by alprenolol, a beta-adrenoceptor antagonist with modest affinity for beta 3-adrenoceptors, but were resistant to ICI-118551 and atenolol. 6. These results indicate that ICI-215001 exhibits beta 3-adrenoceptor agonist activity as demonstrated by relaxations mediated via atypical beta-adrenoceptors in the longitudinal smooth muscle of guinea-pig ileum. Further, the studies demonstrate that ICI-215001 can act as an antagonist at beta 1- and beta 2-adrenoceptors in situations where its intrinsic agonist activity is low.     

(-)-7-羟基-3-羰基-6-[4-苯氧基-3-羟基-1-(E)-丁烯基]-2-氧杂二环[3,3,0]辛烷合成工艺的改进

目的 改进磺前列酮中间体3(S)-烯醇化合物的合成工艺。方法 以双羟化合物为起始原料经硅醚化、选择性氧化、Wittig-Homer反应、水解及立体还原得到3(S)-烯醇化合物。结果 制备得到目标化合物，总收率11％。结论 改进后的合成方法操作简便、易于掌握、反应条件温和、更加适合工业化生产。     

Anti-obesity and anti-diabetic activities of a new beta3 adrenergic receptor agonist, (S)-(Z)-[4-[[1-[2-[(2-hydroxy-3-phenoxypropyl)]amino]ethyl]-1-propenyl] phenoxy] acetic acid ethanedioic acid (SWR-0342SA), in KK-Ay mice.

We investigated the beta-adrenergic receptor (AR) agonistic activities in rats and humans, and the anti-obesity and anti-diabetic activities in KK-Ay mice, of a new beta3-AR agonist, SWR-0342SA ((S)-(Z)-[4-[[1-[2-[(2-hydroxy-3-phenoxypropyl)]amino]ethyl]-1-pro penyl]phenoxy] acetic acid ethanedioic acid). With regards to its beta-AR agonistic activity in rats, SWR-0342SA stimulated the atrial beating rate (beta1-AR activity) and white adipocyte lipolysis (beta3-AR activity), but did not induce uterine muscle relaxation (beta2-AR activity). The beta3-AR agonistic activity of SWR-0342SA was about 20 times stronger than its beta1-AR agonistic activity. Similarly, SWR-0342SA enhanced the accumulation of cAMP in Chinese hamster ovary (CHO) cells expressing human beta1- and beta3-ARs, while having no effect in CHO cells expressing beta2-ARs. Adenylyl cyclase stimulation by SWR-0342SA in CHO cells expressing beta3-ARs was about 35 times higher than that in CHO cells expressing beta1-ARs. With regards to anti-obesity and anti-diabetic activities, SWR-0342SA had no effect on body weight or food intake, but slightly decreased the fat pads weight in KK-Ay mice, an animal model of obesity and non-insulin-dependent diabetes mellitus (NIDDM). On the other hand, SWR-0342SA significantly decreased both blood glucose (to about 46% of control) and serum insulin levels (to about 40% of control) in KK-Ay mice. These results indicated that SWR-0342SA is a selective beta3-AR agonist, and possesses potent anti-diabetic activity, and that the anti-obesity activity is inferior to the anti-diabetic activity.     

(+/-)-1-[[2-(3,4-Dimethoxphenyl)ethyl]amino]-3-(3-methylphenoxy)-2- propanol hydrochloride (bevantolol, NC-1400) as a beta 1-selective adrenoceptor blocker with alpha 1-adrenoceptor blocking activity

Blocking activities of alpha- and beta-adrenoceptors by (+/-)-1-[[2-(3,4-dimethoxyphenyl)-ethyl]amino]-3-(3-methylphenoxy)-2 -propanol hydrochloride (NC-1400) were tested on the isolated muscles, comparing with those of labetalol and atenolol. In blocking the beta 1-adrenoceptor, NC-1400 was slightly more potent than labetalol and atenolol. NC-1400 was about 1/10th as potent as labetalol and about ten times as potent as atenolol in blocking the beta 2-receptor. NC-1400 was beta 1-adrenoceptor selective. NC-1400 was about 1/30th as potent as labetalol in blocking the alpha 1-receptor. NC-1400 did not interact with the alpha 2-adrenoceptor in concentrations up to 10(-5) M. The present results indicate that NC-1400 is the selective beta 1-adrenoceptor blocker with some blocking activity of alpha 1-adrenoceptors.     

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.     

Design and pharmacology of N-[(3R)-1,2,3,4-tetrahydroisoquinolinium- 3-ylcarbonyl]-(1R)-1-(4-chlorobenzyl)- 2-[4-cyclohexyl-4-(1H-1,2,4-triazol- 1-ylmethyl)piperidin-1-yl]-2-oxoethylamine (1), a potent,selective, melanocortin subtype-4 receptor agonist

Synthetic and natural peptides that act as nonselective melanocortin receptor agonists have been found to be anorexigenic and to stimulate erectile activity. We report the design and development of 1, a potent, selective (1184-fold vs MC3R, 350-fold vs MC5R), small-molecule agonist of the MC4 receptor. Pharmacological testing confirms the food intake lowering effects of MC4R agonism and suggests another role for the receptor in the stimulation of erectile activity.     

Salivary secretion evoked by H80/62, (+/-)-1-(4-hydroxyphenoxy)-3-isopropylamino-2-propranol, a new beta 1-selective adrenoceptor agonist.

H80/62, recently introduced as a beta 1-selective adrenoceptor agonist, caused a long-lasting flow of saliva from parotid and submaxillary glands of the rat. The effect of H80/62 was prevented by propranolol or a beta 1-selective blocker. The drug did not exert its effect via the sympathetic postganglionic nerves; and it was not taken up by the neuronal amine pump. Sympathetically decentralized or denervated glands acquired a supersensitivity of the postjunctional type to H80/62.     

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

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

A selective human H(4)-receptor agonist: (-)-2-cyano-1-methyl-3-[(2R,5R)-5- [1H-imidazol-4(5)-yl]tetrahydrofuran-2-y] methylguanidine

A series of 16 compounds related to chiral 4(5)-(5-aminomethyltetrahydrofuran-2-yl)imidazoles (1) have been designed, synthesized, and examined in vitro by radioligand displacement studies and functional assays for both the human H(3)- and H(4)-receptors expressed in SK-N-MC cells. Among them, the (2S,5S)-isomer 1d of amino compounds showed approximately 300-fold higher selectivity at the H(3)-receptor than the H(4)-receptor. On the other hand, (2R,5S)- and (2R,5R)-cyanoguanidines 3b and 3c, in which the amino group of the compounds 1b and 1c was substituted by the cyanoguanidino moiety, bound to the H(4)-receptor with a pEC(50) value of 6.65 and 7.11, respectively, and had >40-fold selectivities over the H(3)-receptor. As such, 3b and 3c are the first selective H(4) receptor agonists.     

3H] A-369508 ([2-[4-(2-cyanophenyl)-1-piperazinyl]-N-(3-methylphenyl) acetamide): an agonist radioligand selective for the dopamine D4 receptor

Tritiation of the dopamine D(4) receptor selective agonist A-369508 ([2-[4-(2-cyanophenyl)-1-piperazinyl]-N-(3-methylphenyl) acetamide) has provided a radioligand for the characterization of dopamine D(4) receptors. [(3)H] A-369508 binds with high affinity to the major human dopamine D(4) receptor variants D(4.2), D(4.4) and D(4.7) (K(d)=1.7, 4, and 1.2 nM, respectively). It also binds to the rat dopamine D(4) receptor, (K(d)=4.4 nM), implying similar binding affinity across human and rat receptors. A-369508 shows >400-fold selectivity over D(2L), >350-fold selectivity over 5-HT(1A) and >700-1,000-fold selectivity over all other receptors tested. Agonist activity determined by inhibition of forskolin-induced cAMP in Chinese hamster ovary cells transfected with the human dopamine D(4.4) receptor (EC(50)=7.5 nM, intrinsic activity=0.71) indicates that A-369508 is a potent agonist at the human dopamine D(4) receptor. Similar data was observed in other functional assays. [(3)H] A-369508 binds to a single, high affinity site on membranes containing the human dopamine D(4.4) receptor. When compared to the D(2)-like antagonist [(3)H] spiperone, competition binding for agonists like dopamine and apomorphine were 2-10-fold more potent with [(3)H] A-369508, while the antagonists clozapine, haloperidol and L-745870 bind with similar affinity to both ligands. Binding to rat brain regions demonstrated that the most abundant area was cerebral cortex (51.2 fmol/mg protein) followed by hypothalamus, hippocampus, striatum and cerebellum. [(3)H] A-369508 is a useful tool to define the localization and physiological role of dopamine D(4) receptors in central nervous system and can facilitate measuring accurate affinities (K(i)) for structure/activity relationship studies designed to identify dopamine D(4) receptor selective agonists.     

Synthesis and structure-activity studies on N-[5-(1H-imidazol-4-yl)-5,6,7,8-tetrahydro-1-naphthalenyl]methanesulfonamide, an imidazole-containing alpha(1A)-adrenoceptor agonist

Structure-activity studies were performed on the alpha(1A)-adrenoceptor (AR) selective agonist N-[5-(1H-imidazol-4-yl)-5,6,7,8-tetrahydro-1-naphthalenyl]methanesulfonamide (4). Compounds were evaluated for binding activity at the alpha(1A), alpha(1b), alpha(1d), alpha(2a), and alpha(2B) subtypes. Functional activity in tissues containing the alpha(1A) (rabbit urethra), alpha(1B) (rat spleen), alpha(1D) (rat aorta), and alpha(2A) (rat prostatic vas deferens) was also evaluated. A dog in vivo model simultaneously measuring intraurethral pressure (IUP) and mean arterial pressure (MAP) was used to assess the uroselectivity of the compounds. Many of the compounds that were highly selective in vitro for the alpha(1A)-AR subtype were also more uroselective in vivo for increasing IUP over MAP than the nonselective alpha(1)-agonists phenylpropanolamine (PPA) (1) and ST-1059 (2, the active metabolite of midodrine), supporting the hypothesis that greater alpha(1A) selectivity would reduce cardiovascular side effects. However, the data also support a prominent role of the alpha(1A)-AR subtype in the control of MAP.     

(+/-)-7-chloro-8-hydroxy-1-(4'-[125I]iodophenyl)-3-methyl-2,3,4,5- tetrahydro-1H-3-benzazepine: a potential CNS D-1 dopamine receptor imaging agent

Synthesis, radiolabeling, and in vitro and in vivo properties of an iodinated benzazepine, (+/-)-7-chloro-8-hydroxy-1-(4'-[125I]iodophenyl)-3- methyl-2,3,4,5-tetrahydro-1H-3-benzazepine, [125I]FISCH, as a potential imaging agent for evaluation of central nervous system (CNS) D-1 dopamine receptors in humans, were investigated. After an iv injection, this benzazepine derivative showed good brain uptake in rats (2.27, 1.40, 0.55% dose/whole brain at 2, 15, and 60 min, respectively). The striatum/cerebellum ratio was high (2.47 at 60 min after the injection). The binding affinity of this agent in rat striatum tissue preparation displayed a Kd of 1.43 +/- 0.15 nM. Competition data (in vitro) showed the following rank order of potency: SCH-23390 greater than (+/-)-FISCH greater than (+/-)-IBZP much greater than apomorphine greater than WB 4010 greater than ketanserin approximately spiperone. The preliminary data suggest that the agent is highly selective for the CNS D-1 receptor.     

Synthesis and preliminary biological studies of 4- and 5-[2-hydroxy-3-(isopropylamino)propoxy]benzimidazoles: selective beta2 adrenergic blocking agents.

Benzimidazoles carrying the 2-hydroxy-3-(isopropylamino)propoxy side chain at either the C-4 or C-5 ring positions were synthesized and investigated for beta-adrenergic blocking activity. Both compounds demonstrated beta2 selectivity when evaluated in guinea pig atrial and tracheal preparations. The C-4 isomer was 17 times more selective toward tracheal tissue, and its overall potency was roughly comparable to that of propranolol. beta2 selectivity of the C-5 isomer was minimal, with a potency about one-hundredth that of propranolol.     

Synthesis and 5-HT2A, 5-HT1A and alpha1-binding affinities of 2-[2-Hydroxy-3-(pyridin-3-yl-methyl)amino]-, 2-[2-hydroxy-3-(2-pyridin-2-yl-ethyl)amino]- and 2-[2-hydroxy-3-(4-N-methyl-piperazin-1-yl)-amino]propoxybenzaldehyde-O-(substituted) benzyl oximes

Some oxime ether-substituted aryloxypropanolamines 3-5, structurally related to the active metabolite 2 of sarpogrelate 1, were synthesized and tested for their affinities at 5-HT2A and 5-HT1A serotoninergic receptors as well as at the alpha1-adrenoceptor. The results show that the compounds possess, at least partially, the ability of the model compounds 1 and 2 to interact with the 5-HT2A-receptors; they have the same selectivity towards 5-HT2A receptors vs alpha1-adrenoceptors.     

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 antiviral activity of 9-[4-hydroxy-3-(hydroxymethyl)but-1-yl]purines

Alkylation of 2-amino-6-chloropurine with 5-(2-bromoethyl)-2,2-dimethyl-1,3-dioxane (5) provided 2-amino-6-chloro-9-[2,(2,2-dimethyl-1,3-dioxan-5-yl)ethyl]purine (6) in high yield. This aminochloropurine 6 was readily converted to the antiviral acyclonucleoside 9-[4-hydroxy-3-(hydroxymethyl)but-1-yl]guanine (1) and to its 6-chloro (10), 6-thio (11), 6-alkoxy (12-17), 6-amino (20), and 6-deoxy (21) purine analogues. The guanine derivative 1 was converted to its xanthine analogue 9. Similarly, alkylation of 6-chloropurine with 5 provided a route to 8, the hypoxanthine analogue of 1. Of these 9-substituted purines, the guanine derivative 1 showed the highest activity against herpes simplex virus types 1 and 2 in cell cultures, and in some tests it was more active than acyclovir, with no evidence of toxicity for the cells. A series of monoesters (30-33) and diesters (24-27, 29) of 1 were prepared, and some of these also showed antiherpes virus activity in cell cultures, the most active ester being the dihexanoate 27.     

Synthesis and antibacterial activity of fused 1, 2, 4-triazolo[4, 3-a]quinoxaline and oxopyrimido[2', 1':5, 1]-1, 2, 4-triazolo[4, 3-a]quinoxaline derivatives

A new series of potential antibacterial agents having tricyclic 1, 2, 4-triazolo-[4, 3-a] quinoxaline fused with one or more heterocyclic rings was synthesized via several routes. The tricyclic 1-amino-4-chloro-1, 2, 4-triazolo[4, 3-a] quinoxaline (2 ) and tetracyclic 1, 6-diamino-bis-1, 2, 4-triazolo[4, 3-a:3, 4-c] quinoxaline (3) were synthesized from 2, 3-dichloroquinoxaline (1) with two or four equivalents of thiosemicarbazide, respectively. Compound 2 was allowed to react with different aldehydes, alkoxides, cyclic amines, phenyl isothiocyanate, and t-butyl isocyanate to afford the corresponding quinoxaline derivatives. Moreover, compound 2 reactedwithhydrazine hydrate to give compound 4 which was cyclized by carbondisulfide inalcoholic potassium hydroxide to give the tetracyclic compound 5. Compound 2 was subjected to another cyclocondensation reaction using diethyl ethoxymethylene malonate (DEMM), dimethyl acetylenedicarboxylate (DMAD), and ethyl cyanoacetate to give the tetracyclic compounds 18, 20, and 21, respectively. All the synthesized compounds were evaluated in vitro for antibacterial activity; compounds 18 and 20 were found to display the greatest antibacterial activities. Structural identification was provided by elemental analyses, IR, and (1)H-NMR spectroscopy.