An emerging trend in small-molecule pharmaceuticals, generally composed of nitrogen heterocycles (N-heterocycles), is the incorporation of aliphatic fragments. Derivatization of the aliphatic fragments to improve drug properties or identify metabolites often requires lengthy de novo syntheses. Cytochrome P450 (CYP450) enzymes are capable of direct site- and chemo-selective oxidation of a broad range of substrates but are not preparative. A chemoinformatic analysis underscored limited structural diversity of N-heterocyclic substrates oxidized using chemical methods relative to pharmaceutical chemical space. Here, we describe a preparative chemical method for direct aliphatic oxidation that tolerates a wide range of nitrogen functionality (chemoselective) and matches the site of oxidation (site-selective) of liver CYP450 enzymes. Commercial small-molecule catalyst Mn(CF₃-PDP) selectively effects direct methylene oxidation in compounds bearing 25 distinct heterocycles including 14 out of 27 of the most frequent N-heterocycles found in U.S. Food and Drug Administration (FDA)-approved drugs. Mn(CF₃-PDP) oxidations of carbocyclic bioisostere drug candidates (for example, HCV NS5B and COX-2 inhibitors including valdecoxib and celecoxib derivatives) and precursors of antipsychotic drugs blonanserin, buspirone, and tiospirone and the fungicide penconazole are demonstrated to match the major site of aliphatic metabolism obtained with liver microsomes. Oxidations are demonstrated at low Mn(CF₃-PDP) loadings (2.5 to 5 mol%) on gram scales of substrate to furnish preparative amounts of oxidized products. A chemoinformatic analysis supports that Mn(CF₃-PDP) significantly expands the pharmaceutical chemical space accessible to small-molecule C-H oxidation catalysis.

2013-12-01·Molecules and cells3区 · 生物学

Administration of Mesenchymal Stem Cells and Ziprasidone Enhanced Amelioration of Ischemic Brain Damage in Rats

3区 · 生物学

Article

作者: Eun Shin Lee ; Sung Goo Kang ; Kyung-Yoon Kam ; Seung Eun Baek ; Phatcharida Kaengkan ; Ji Yeong Kim ; Byung-Rok Do

Ziprasidone is a benzisothiazolyl piperazine derivative that was developed from the chemically related antipsychotic drug tiospirone, and it improves neurological functions of the ischemic brain and is effective in treatment of schizophrenia. Mesenchymal stem cells (MSCs) are considered as a leading candidate for neurological regenerative therapy because of their neural differentiation properties in damaged brain. We investigated whether the transplantation of neural progenitor cells (NPCs) derived from adipose mesenchymal stem cells combined with ziprasidone enhances neuroprotective effects in an animal model of focal cerebral ischemia. In combination therapy groups, significant reduction of infarct volume and improvement of neurological functions were observed at 3 days after middle cerebral artery occlusion (MCAO) compared with monotherapy. Co-administration of ziprasidone and NPCs enhanced the anti-apoptotic effect and reduced the number of terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL)-positive apoptotic cells compared with the NPCs alone group at 7 days after MCAO. Ziprasidone or the combination of ziprasidone and NPCs induced the expression of endogenous neurotrophic factor gene brain-derived neurotrophic factor (BDNF), nerve growth factor (NGF), and glial cell-derived neurotrophic factor (GDNF). The immunohistochemical investigation revealed that the ziprasidone and NPCs attenuated the increased intensity of microglial marker (Iba-1) in the infarcted cortical area. Moreover, the number of transplanted NPCs on day 7 with combination therapy was significantly higher than with NPCs alone. These effects might be responsible for improved functional behavior and increased survival of NPCs. Our finding indicates that combination therapy of ziprasidone and NPCs enhances neuroprotection against ischemic brain injury.

2011-03-01·Expert review of clinical pharmacology2区 · 医学

Oral ziprasidone in the treatment of patients with bipolar disorders: a critical review

2区 · 医学

Review

作者: Valsecchi, Paolo ; Sacchetti, Emilio ; Galluzzo, Alessandro

Ziprasidone, a benzisothiazolyl piperazine derivative of tiospirone, is a second-generation antipsychotic with high-affinity antagonism for 5-hydroxytryptophan (5HT)(2A), 5HT(2C), 5HT(1D) and D(2) receptors, pre- and post-synaptic agonism for 5HT(1A) receptors, and inhibition of reuptake for serotonin and norepinephrine. Initially approved for the treatment of adults with schizophrenia, ziprasidone has more recently received supplementary indications for acute manic and mixed episodes and as maintenance therapy for people affected by bipolar disorder. Based on MEDLINE citations up to November 2010 and hand-searched references, this article relating to ziprasidone addresses its short- and long-term efficacy and safety, according to the results of randomized clinical trials, open-label studies and real-world experiences. Emerging evidence indicates that in patients with bipolar disorder, ziprasidone provides valid efficacy and remarkable safety when administered alone for the treatment of manic and mixed episodes. The same applies when ziprasidone is administered in combination with lithium or valproate for the prevention of affective relapses and recurrences. Any conclusion on the potential of ziprasidone as an antidepressant should be postponed because of insufficient evidence.

100 项与 Tiospirone 相关的药物交易

登录后查看更多信息