Fidarestat. Sanwa Kagaku/NC Curex/Sankyo

Fidarestat is an aldose reductase inhibitor being co-developed by Sanwa Kagaku, NC Curex (a joint venture company created by Japan Energy and Kaken) and Sankyo, for the potential treatment of diabetic neuropathy.     

Indacaterol Novartis/skyePharma

In collaboration with SkyePharma, Novartis is developing a multidose dry powder inhaler formulation of indacaterol, a long-acting beta2 agonist and bronchodilator, for the potential treatment of asthma and chronic obstructive pulmonary disease. In January 2006, Novartis expected phase III clinical trials to start in early 2006, with submission planned for 2007.     

Telbivudine/Torcitabine Idenix/Novartis

Idenix (formerly Novirio) and Novartis are developing two beta-L-deoxynucleosides, telbivudine and torcitabine, for the potential treatment of hepatitis B virus infection. Phase III trials of telbivudine were underway by August 2002 and phase I/II trials of the torcitabine prodrug, valtorcitabine, were ongoing in November 2003.     

PTK/ZK (Novartis)

PTK/ZK, a VEGF receptor tyrosine kinase inhibitor, is under development by Novartis AG and Schering AG as an inhibitor of angiogenesis for the potential treatment of various cancers.     

Fingolimod. Mitsubishi Pharma/Novartis

Mitsubishi Pharma Corp and Novartis AG are developing fingolimod, an orally active immunosuppressant affecting lymphocyte re-circulation, for the potential prevention of transplant rejection and the treatment of autoimmune diseases, including multiple sclerosis. Fingolimodis a synthetic sphingosine analog that becomes phosphorylated in vivo and acts as a sphingosine-1-phosphate receptor agonist.     

CS-834 (Sankyo)

CS-834, a carbapenem antibiotic from Sankyo, is in phase II clinical trials for respiratory and urinary tract infections. It is the orally active prodrug of R-95867, to which it is rapidly converted, and is therefore of particular interest as there are, as yet, no oral carbapenems commercially available. CS-834 demonstrated a better overall profile against Gram-positive and Gram-negative species, such as Staphylococcus aureus, Escherichia coli and Klebsiella pneumoniae, compared with several cephalosporins, including cefdinir and cefditoren pivoxil when administered orally in mice. Only Pseudomonas and Enterococcus species showed low susceptibility to the compound.     

IL-1 trap. Regeneron/Novartis

Regeneron and Novartis are co-developing the interleukin (IL)-1 antagonist IL-1 trap for the potential treatment of rheumatoid arthritis. In July 2002, a phase II trial was initiated and results are expected mid-2003.     

BMS-232632 (Novartis/Bristol-Myers Squibb)

BMS-232632, an azapeptide HIV protease inhibitor, is in development by Bristol-Myers Squibb (BMS), under license from Novartis, as a potential treatment for HIV/AIDS [248556]. Early preclinical work was carried out by Novartis [248556]. BMS-232632 was developed as part of a series of compounds (as CGP-73547) and evaluated against drug-resistant strains of HIV; the compounds in this series belong to a series of azadipeptide analogs and are bis(L-tert-leucine) derivatives that exhibit good antiviral activity and satisfactory pharmacokinetic profiles [297907]. Novartis subsequently discontinued evaluation of the compound in November 1999 [347827]. Phase II trials had already begun by July 1999 [334335] and BMS expects NDA filing to take place in 2001 [358937]. Use of BMS-232632 in combination with other antiretroviral agents has demonstrated that it may be used in combination with a variety of nucleoside analogs and protease inhibitors [298464]. It is thought to have a genotypic resistance profile that differs from that of other protease inhibitors [302157]. In February 1999, Lehman Brothers predicted the drug had a 30% probability of reaching market, with an estimated first launch date in 2001. The analysts predicted peak sales would occur in 2007, with sales of $500 million in the US and $300 million in the rest of the world at that time [319225].     

SGS-742 Novartis

SGS-742, a GABA(B) antagonist, is being developed by Saegis, under license from Novartis, for the potential treatment of mild cognitive impairment and Alzheimer's disease (AD). In May 2004, Saegis began enrollment in a phase II trial of SGS-742 in mild-to-moderate AD patients.     

Iralukast Novartis AG

Iralukast is an LTD(4) and LTE(4) antagonist under development by Novartis and in phase II clinical trials as a potential treatment for asthma [244117], [177071]. In a double-blind, placebo-controlled trial in 16 patients with mild to moderate asthma, a single 1.5 mg inhaled dose of iralukast reduced the incidence of exercise-induced bronchiospasm and was well-tolerated [272161]. Novartis has an agreement with Rhone-Poulenc Rorer to use its Ultrahaler delivery system for iralukast and phase II trials are underway [220836]. The agreement also involves the development of further related compounds and delivery systems.     

LC-ESI-MS/MS快速测定人血浆中匹伐他汀浓度

目的建立一种快速灵敏测定人体血浆中匹伐他汀浓度的高效液相色谱串联质谱检测方法。方法以AgilentC18柱（4.6mm×150mm,3.5μm）为色谱柱,流动相为甲醇-0.005mol·L^-1甲酸铵水溶液-乙腈-1%甲酸水溶液（7.5∶2.5∶70∶20）;流速：0.5mL·min^-1,柱温：40℃。采用选择反应监测（SRM）对匹伐他汀（m/z422.2→290.2）和内标瑞舒伐他汀（m/z482.2→258.2）进行测定。结果匹伐他汀高（80μg·L^-1）、中（50μg·L^-1）、低（0.25μg·L^-1）3个浓度的平均回收率RSD均小于15%;线性范围为：0.1-100μg·L^-1,回归方程为Y=1.2226X-1.0561×10^-4,r=0.9960。结论该方法灵敏、准确、简单、快速,可用于匹伐他汀临床血药浓度监测和药动学研究。     

匹伐他汀钙的合成

2-环丙基-4-（4-氟苯基）-喹啉-3-羧酸乙酯经KBH4／ZnCl2还原、溴化、制得膦叶立德后，与（3R，5S）-6-氧代-3，5-二羟基-3，5．0-亚异丙基己酸叔丁酯进行Wittig-Homor反应、脱保护并内酯化、水解成盐制得HMG CoA还原酶抑制剂类降血脂药物匹伐他汀钙，总收率约31％。     

Pimecrolimus (Novartis)

Pimecrolimus, an ascomycin macrolactam derivative, is an inhibitor of T-cell and mast cell activation under development by Novartis for the potential treatment of psoriasis and allergic dermatitis. Novartis is developing both topical and oral formulations of the compound. By December 1998, the topical form of the compound was in phase III trials and the oral form was in phase II trials. Phase III trials were initiated in July 1999 for the treatment of atopic dermatitis. In December 1998, Warburg Dillon Read predicted sales of SFr 30 million in 2000 rising to SFr 184 million in 2002. In March 1999, Credit Suisse First Boston predicted sales of 10 million USD in 2001 rising to 90 million USD in 2003.     

Lumiracoxib (Novartis)

Lumiracoxib, an inhibitor of cyclooxygenase 2 (COX-2), is under development by Novartis for the potential treatment of osteoarthritis, rheumatoid arthritis and pain. By late December 2000, phase III trials had been initiated and were ongoing in December 2001.     

LAF-237 (Novartis)

Novartis is developing LAF-237, one of a series of orally active dipeptidylpeptidase IV inhibitors, as a potential once daily therapeutic agent for type 2 diabetes. Phase III trials began in the first quarter of 2004.     

Methylphenylethynylpyridine (MPEP) Novartis

SIBIA and Novartis are investigating the use of excitatory amino acid agonists and antagonists for the metabotropic receptor and the ionotropic receptors AMPA and NMDA. Preliminary experiments indicate they may have potential in the treatment of epilepsy, stroke, anxiety, pain and neurodegenerative disease. Methylphenylethynylpyridine (MPEP) is the lead compound in the series [347212]. Other compounds in the series that arose from the collaboration were SIB-1893, and its equipotent analog, SIB-1757, both of which are subtype-selective, potent antagonists of mGluR5. Chemical derivation of SIB-1893 resulted in the discovery of MPEP, a selective, systemically active noncompetitive mGluR5 antagonist. Studies using these agents have yielded data to support the involvement of mGluR5 in inflammatory mechanical hyperalgesia [311829], [311828], [311823], [311880], [319655]. MPEP is the most potent of these compounds with an IC50 value of 12 nM for inhibition of quisqualate-stimulated phosphoinositide hydrolysis in recombinant human mGluR5a-expressing cells. MPEP exhibited no cross reactivity with mGluR1 and other mGluRs, or against representative NMDA, AMPA and kainate receptors up to concentrations of 100 microM. The compound, administered orally (100 mg/kg) produced a 70% reversal of mechanical hyperalgesia in the Freund's complete adjuvant model of inflammatory pain [319261]. By October 1999, investigations with SIB-1757 and SIB-1893 had been discontinued in favor of MPEP [347212].     

EPO-906 (Novartis)

Novartis Pharma AG is developing EPO-906, an intravenous formulation microtubular depolymerization inhibitor (microtubule stabilizer), for the potential treatment of cancer.     

TCH-346 (Novartis)

TCH-346, an anti-apoptotic compound, is under development by Novartis for the potential treatment of Parkinson's disease (PD) and motor neuron disease [271447,342937]. By September 1999, phase I clinical trials for PD were underway [342937]. The compound was discovered in a screen for molecules with both norepinephrine uptake and MAO inhibiting properties but, although it had anti-apoptotic properties, it did not inhibit MAOA or MAO-B [333136,332004]. The compound increases lifespan in the progressive motorneuropathy mouse model and prevents ischemia in models of ischemia and seizure [288893]. In vivo, it shows neurorescuing and anti-apoptotic properties in PC12 cells and cerebellar granule cells, among others, at concentrations of 0.1 pM to 10 microM, suggesting that its action might prove potentially useful against Alzheimer's and/or Parkinson's disease [332004]. The compound has also shown neurorescuing properties in rat pups after axotomy, rat hippocampal CA1 neurons after transient ischemia/hypoxia and mouse nigral dopaminergic (DA) neurons after treatment with MPTP in doses ranging between 0.0003 and 0.1 mg/kg po or sc, depending on the model [333136]. Data presented by the University of Nijmengen and the Free University of Amsterdam show that TCH-346 improves the behavioral and enzymatic outcome in the rat 6-OH-dopamine model of Parkinson's disease. TCH-346 (0.0014 mg/kg sc bid) prevented abnormal stepping (open field test) and prevented increases in fore and hind-paw retraction time. TCH-346 also improved acquisition in the Morris water maze task and, at doses between 0.0014 and 0.14 mg/kg, prevented reduction in tyrosine hydroxylase immunoreactivity [345259]. Affinity binding studies with TCH-346 showed that GAPDH is the target [294902,283200]. Differential display RT-PCR also showed that protein-isoaspartyl-methyl transferase is induced by the drug [283200].