美罗培南三水合物的合成

目的合成碳青霉烯类抗生素美罗培南.方法以羟脯氨酸为起始原料,经5步反应合成得到侧链(2S,4S)-二甲氨基甲酰基-4-巯基-1-(4-硝基苯甲氧羰基)吡咯烷(V),V与(1R,5R,6S)-2-(二苯氧基磷酰氧基)-6-[(R)-1-羟乙基]-1-甲基碳青霉-2-烯-3-羧酸对硝基苄酯(Ⅵ)经取代、氢化、大孔吸附树脂柱色谱纯化得到美罗培南三水合物,总收率为13.9%(以羟脯氨酸计).结果与结论合成了美罗培南三水合物,其结构经质谱、核磁共振氢谱和热重分析确证.     

美罗培南新脂溶性前药的合成和药物动力学研究

为了提高美罗培南口服吸收,本课题合成并研究了一系列在其羰基和吡咯烷基上引入脂溶性修饰基前药.在这些前药中,对特戊酰甲氧基-(1R,5S,6S)-2-[(3S,5S)-5-(N,N-二甲氨基甲酰基-1-(异丁酰氧甲氧基羰基)吡咯烷-3-硫代-6-[(1R)-1-羟乙基]-1-甲基羧苄青霉素-2-烯-3-羧酸酯(4)和1-...     

抗生素Doripenem

Doripenem(多尼培南)是广谱碳青酶烯类抗生素,化学名为(4R,5S,6S)-3-[((3S,5S)-5-[[(氨基磺酰)氨基]-甲基]-3-吡咯烷基)硫]-6-[(1R)-1-羟基乙基]-4-甲基-7-氧代-1-氮杂双环[3.2.0]庚-2-烯-2-甲酸一水合物.注射用Doripenem(商品名:Doribax)由美国强生公司研发,于 2007年10月15日被美国FDA批准用于治疗复杂性腹内感染和泌尿道感染,包括肾盂肾炎.多尼培南作用于青霉素结合蛋白(PBPs),通过抑制细菌细胞壁的生物合成发挥抗菌作用.     

Invanz

[通用名称]ertapenem,厄他培南 [化学名称][4R-[3(3S*,5S*)4α,5β,6β(R*)]]-3-[[5-[(3-羧基苯基)氨基]3-吡咯烷基]硫]-6-(1-羟乙基)4-甲基-7-氧-氮杂二环[3.2.0]庚-2-烯-2-羧酸单钠盐.     

美洛培南等抗生素对超广谱β-内酰胺酶的稳定性及抑酶效应研究

用紫外分光光度法,以其它β-内酰胺抗生素为对照,研究美洛培南对6种标准超广谱β-内酰胺酶(TEM-3,TEM-4,TEM-5,SHV-2,SHV-4,SHV-5)的稳定性及抑酶作用.美洛培南、亚胺培南、拉氧头孢和头孢西丁对6种标准超广谱β-内酰胺酶均高度稳定.氨曲南对6种酶的稳定性较好,其相对水解率不超过13%;青霉素及一、二、三代头孢菌素对6种酶均不稳定,大多数相对水解率超过20%.美洛培南和亚胺培南对6种β-内酰胺酶具有良好抑制作用,且抑制程度与抑制剂浓度有关.     

厄他培南钠的合成

目的合成厄他培南钠。方法以4R-[4a,5b,6b(R*)]-3-二苯基磷酰氧基-6-(1-羟基乙基)-4-甲基-7-氧代-1-氮杂双环[3.2.0]庚-2-烯-2-羧酸对硝基苄酯(MAP)和3-[(2S,4S)-4-巯基吡咯烷-2-羰酰胺基]苯甲酸盐酸盐(厄他培南侧链)为起始原料,经缩合,氢化得厄他培南钠。结果厄他培南钠工艺总收率67%,纯度99.3%。结论本工艺操作简单,收率高,纯度高,适合工业化生产。     

碳青霉烯抗生素对质粒介导β-内酰胺酶的稳定性及抑酶效应研究

用紫外分光光度法，以其它β—内酰胺抗生素为对照，研究碳青霉烯类抗生素亚胺培南、美洛培南和帕尼培南对14种标准β—内酰胺酶(TEM—1，TEM—2，TEM—3，TEM—5，SHV—1，SHV—2，SHV—4，SHV—5，PSE—1，PSE—2，PSE—3，OXA—1，OXA—2，OXA—3)的稳定性及抑酶作用。亚胺培南、美洛培南、帕尼培南和头孢西丁对14种标准β—内酰胺酶均高度稳定。所有抗生素对超广诺β—内酰胺酶(TEM—3、TEM—5、SHV—2、SHV—4、SHV—5)的IC50低于3μmol/L；但对广谱酶(TEM—1，TEM—2，SHV—1，OXA)的IC50超过100μmol/L。整体上美洛培南对14种β—内酰胺酶的抑制作用强于亚胺培南和帕尼培南。     

新的注射用1-β-甲基碳青霉烯BO-2727的药代动力学和安全性及其对粪菌丛的影响

BO-2727是由日本东京Banyu制药公司开发的注射用1-β-甲基碳青霉烯抗生素.化学名:(1R,5S,6S)-6-[(R)-1-羟乙基]-2-[(3S,5S)-5-[(R)-l-羟基-3-N-甲基-氨丙基]吡啶烷-3-基-硫]-1-甲基1碳青霉-2-烯-3-羧酸盐酸盐水合物(图1).BO-2727对革兰阳性菌和包括绿脓杆菌在内革兰阴性菌具有强大抗菌活性.实验动物毒性研究显示,它与已用于临床的亚胺培南/西司他丁钠一样安全.BO-2727对人肾脱氢肽酶(DHP-I)稳定,不需要合用像西司他丁钠那样的DHP-I酶抑制剂.BO-2727在恒河猴和黑猩猩中显示优越药代动力学性质,即它的AUC和血浆清除半衰期(T_1/2β)比亚胺培南/西司他丁或meropenem的大和长.鉴于临床前试验所验证中的BO-2727临床有效性,Nakashima在健康志愿者中进行了评价单剂量和多剂量下的耐受性和药代动力学研究.     

药品行政保护品种介绍——心血管系统药物(三)(续二)

普伐他丁钠通用名:普伐他丁钠(pravastatin sodium),商品名:美百乐镇(Mevalotin)片剂.化学名:[+]-(3R,5R)-3,5-二羟基-7{(1S,2S,6S,8S,8 α R)-6-羟基-2-甲基-8[(S)-2-甲基丁酰氧基]-1,2,6,7,8,8 α-六氢-1-萘基}庚酸钠.     

高效毛细管电泳法研究美洛培南和亚胺培南/西司他丁在腹膜透析液中的稳定性

目的:用高效毛细管电泳法研究美洛培南和亚胺培南/西司他丁在腹膜透析液中的稳定性。方法:运行缓冲液为0.03 mol.L-1磷酸硼砂缓冲液和0.05 mol.L-1的十二烷基硫酸钠,pH8.5;操作电压20 kV,检测波长200 nm。结果:美洛培南、亚胺培南、西司他丁的线性范围为100～1000 μg.ml-1。结论:美洛培南在腹膜透析液中不稳定,5℃放置5小时后含量下降到90%以下。亚胺培南较美洛培南在腹膜透析液中稳定,在5℃时可放置14小时。西司他丁5℃放置14小时含量只下降6%。pH变化在0.4以内。     

Allosteric interaction of zinc with recombinant alpha(1)beta(2)gamma(2) and alpha(1)beta(2) GABA(A) receptors

In a recent study we have provided evidence that inhibition of native GABA(A) receptors by zinc depends primarily on the allosteric modulation of receptor gating. Both the kinetics and the sensitivity of the GABA(A) receptor to zinc depend on subunit composition, especially on the presence of the gamma(2) subunit. To analyze the mechanism of action of zinc its effects have been tested on recombinant alpha(1)beta(2)gamma(2) and alpha(1)beta(2) receptors expressed in HEK 293 cells. The currents produced by ultrafast application of GABA have been measured to assess the impact of zinc ions on GABA(A) receptor gating with resolution corresponding to the time scale of synaptic currents. While, as expected, zinc markedly reduced the peak amplitude of alpha(1)beta(2)-mediated currents, its effect on kinetics was significantly different from that observed for alpha(1)beta(2)gamma(2). In particular, unlike alpha(1)beta(2)gamma(2), zinc did not affect the onset of alpha(1)beta(2)-mediated responses. Moreover, zinc increased the extent of desensitisation of alpha(1)beta(2)gamma(2) receptors and reduced desensitisation of alpha(1)beta(2) ones. Quantitative analysis suggests that zinc exerts an allosteric modulation on both alpha(1)beta(2)gamma(2) and alpha(1)beta(2) receptors. Zinc effects on alpha(1)beta(2)gamma(2) were qualitatively similar to those reported for native receptors.     

(S)-(-)-氨磺必利-D-(-)-酒石酸盐的合成

目的研究（S）-（-）-氨磺必利-D-（-）-酒石酸盐的制备方法。方法以4-氨基-2-甲氧基-5-巯基苯甲酸为原料,经乙基化、氧化得4-氨基-2-甲氧基-5-乙基磺酰基苯甲酸（4）,另由1-乙基-2-氨甲基吡咯烷经D-（-）-酒石酸拆分得S-（-）-1-乙基-2-氨甲基吡咯烷（6）,4与6缩合制得S-（-）-氨磺必利（7）,再与D-（-）-酒石酸成盐制得目标物S-（-）-氨磺必利-D-（-）-酒石酸盐（1）。总收率达25%（以4-氨基-2-甲氧基-5-巯基苯甲酸计算）。结果所得产物经元素分析,红外光谱、核磁共振谱及质谱确证了结构。结论本方法原料易得,反应条件温和,产品质量易控制。     

alpha-glucosidase (CHO) (Genzyme)

Genzyme General is developing recombinant human alpha-glucosidase, produced in mammalian cell culture, as a potential treatment for Pompe disease. By July 2004, enrollment was completed in two clinical trials and an observational study in adults. Genzyme was planning to file for regulatory approval in Europe during 2004, followed by filings in the US and Japan in mid-2005.     

(S)-oxybutynin (Sepracor)

Sepracor is developing (S)-oxybutynin, a single-isomer version of Alza's Ditropan (racemic oxybutynin), a muscarinic acetylcholine receptor antagonist, as a potential treatment for urinary incontinence.     

Developmental toxicity of di-(C(7)-C(9) alkyl) phthalate and di-(C(9)-C(11) alkyl) phthalate in the rat

Two phthalate esters, di-(C(7)-C(9) alkyl) phthalate (D79P) and di-(C(9)-C(11) alkyl) phthalate (D911P), have been assessed for their potential to cause developmental toxicity in the rat. Groups of 22 timed-mated Sprague-Dawley rats were administered 250, 500, or 1000 mg/kg D79P or D911P daily by oral gavage (5 ml/kg) between gestation days (GD) 1 and 19. Control animals received the vehicle (olive oil) alone. On GD20, the animals were sacrificed and the fetuses examined. Treatment resulted in no signs of maternal toxicity, as assessed by adjusted maternal bodyweight gain throughout gestation and clinical examinations, and no effects upon litter size, fetal survival or bodyweight. Pups of the high dose D79P and intermediate and high dose D911P groups showed increased incidences of supernumerary lumbar ribs. There was a significant increase in dilated renal pelves in pups of the low dose D79P and high dose D911P groups, but only for D911P was there a significant trend. Consequently, the no observed adverse effect level (NOAEL) for maternal toxicity for both D79P and D911P is 1000 mg/kg/day. The NOAEL values for developmental toxicity are 500 mg/kg/day D79P and 250 mg/kg/day D911P.     

Psychopharmacological profile of 1-(m-(trifluoromethyl) phenyl) piperazine (TFMPP)

The effect of TFMPP, an agonist of the 5-HT1b receptors, was studied in mice on several psychopharmacological parameters. In contrast to imipramine-like drugs, TFMPP neither antagonized reserpine-induced hypothermia nor increased yohimbine-induced toxicity. Similarly to imipramine-like drugs, TFMPP antagonized oxotremorine-induced hypothermia and was active in the behavioural despair test. In addition, TFMPP normalized a social behavioural deficit induced by isolation. The effects of TFMPP on oxotremorine-induced hypothermia in the behavioural despair test and in the isolation-induced social behavioural deficit are all antagonized by d-1 propranolol. It is concluded that TFMPP seems to possess psychotropic activity resembling only in part that of imipramine-like drugs and that these actions may be mediated through 5-HT1b receptors.     

Inhibition of Poly(ADP-Ribose)Polymerase (PARP)

Recently, studies of B-cell physiology have continued to provide new and surprising insights into the nature of autoimmunity, highlighting novel potential immunointervention strategies. The meeting on ‘B cells and autoimmunity: new concepts and therapeutic perspectives’ brought together basic scientists and clinicians with research interests in a range of autoimmune diseases. Recent advances in different facets of B-cell biology were discussed in the prospect of understanding autoimmunity, and significant advances in our understanding of the mechanisms that regulate the autoimmune response at the B cell-level were described. Even though no single message emerged, it is clear that the B lymphocyte is truly destined to become a therapeutic target for the treatment of autoimmune disease.     

Two-generation reproduction toxicity studies of di-(C(7)-C(9) alkyl) phthalate and di-(C(9)-C(11) alkyl) phthalate in the rat

Di-(C(7)-C(9) alkyl) phthalate (D79P) and di-(C(9)-C(11) alkyl) phthalate (D911P), based on high-normality linear oxo-alcohols, have been assessed for their impact upon reproductive performance in Sprague-Dawley rats. Rats were continuously exposed to either D79P or D911P at dietary levels of 0%, 0.1%, 0.5%, or 1.0% over two generations. Selected F(0) offspring (F(1) generation) were exposed to the same dietary concentration of D79P or D911P as the respective F(0) animals, and were mated to produce F(1) offspring. Both D79P and D911P markedly reduced body weight gain in F(0) and F(1) adult males at the highest dose, but females were affected to a lesser extent. There was no impairment of fertility, fecundity, or development in either generation, but body weights of offspring in the 1.0% D79P and 1.0% D911P groups were slightly and transiently reduced over the weaning period. Although decreases in the weight of several organs were accounted for by depressed body weight, ovary weights were reduced in both generations exposed to 1.0% D79P, and epididymidal weights were slightly reduced in adults of both generations exposed to 1.0% D911P. However, ovarian function-assessed by the oestrus cycle and mating behaviour-and epididymidal sperm concentration, motility, and morphology were unaffected by either substance. Treatment resulted in liver changes, particularly in males, characterised by increased liver weight in young animals, histopathologic changes and reduced organ weight in mature animals, and an increase in palmitoyl CoA oxidase activity. In conclusion, neither D79P nor D911P impaired reproductive function in rats when administered in the diet at levels that induce systemic toxicity, and the NOAEL for effects on reproduction in the rat is 0.5% for both D79P and D911P.     

Mechanisms of anabolic androgenic steroid modulation of alpha(1)beta(3)gamma(2L) GABA(A) receptors

Modulation of GABA(A) receptors induced by both anabolic androgenic steroids (AAS) and the benzodiazepine (BZ) site agonist, zolpidem, show equivalent dependence upon gamma subunit composition suggesting that both compounds may be acting at a shared allosteric site. Here we have characterized modulation induced by the AAS, 17alpha-methyltestosterone (17alpha-MeT), for responses elicited from alpha(1)beta(3)gamma(2L) GABA(A) receptors and compared it to modulation induced by the BZ site agonists, zolpidem and diazepam. For responses elicited by brief pulses of 20 microM GABA, both the AAS and the BZ site compounds significantly increased the peak current amplitudes and total charge transfer, although 17alpha-MeT was an appreciably weaker agonist than either diazepam or zolpidem at alpha(1)beta(3)gamma(2L) receptors. Neither class of modulator enhanced peak current amplitudes for responses elicited by mM concentrations of GABA. BZ site compounds altered time constants of deactivation, desensitization, and recovery from desensitization, however 17alpha-MeT had no overall effect on these parameters. Experiments in which 17alpha-MeT and BZ site ligands were applied concomitantly indicated that potentiation elicited by 17alpha-MeT and zolpidem were additive and that potentiation by 17alpha-MeT could be elicited in the presence of concentrations of flumazenil that blocked BZ potentiation. Finally, kinetic modeling suggests that while effects of 17alpha-MeT can be simulated by altering receptor affinity, the data for these alpha(1)beta(3)gamma(2L) receptors were best fitted by simulations in which 17alpha-MeT increases transitions into the singly liganded open state. Taken together, our results suggest that 17alpha-MeT does not act at the high-affinity BZ site, but may elicit some of its effects at the low affinity BZ site or at a novel site.