Eckhard Ottow

The type IV phosphodiesterase specific inhibitor mesopram inhibits experimental autoimmune encephalomyelitis in rodents

Experimental autoimmune encephalomyelitis (EAE) is an autoimmune disease with pathological features reminiscent of those seen in multiple sclerosis and thus serves as an animal model for this disease. Inhibition of type IV phosphodiesterase (PDE IV) in animals with this disease has been shown to result in amelioration of disease symptoms. Here we describe the immunomodulatory activity of the novel potent and selective PDE IV inhibitor mesopram. In vitro, mesopram selectively inhibits the activity of type 1 helper T (Th1) cells without affecting cytokine production or proliferation of type 2 helper T (Th2) cells. Administration of mesopram to rodents inhibits EAE in various models. Clinically, EAE is completely suppressed by mesopram in Lewis rats. This is accompanied by a reduction of inflammatory lesions in spinal cord and brain. RT-PCR analysis revealed a marked reduction in the expression of interferon-gamma (IFN-gamma) and tumor necrosis factor-alpha (TNF-alpha) in the brains of these animals. Furthermore, the ex vivo production of Th1 cytokines by activated spleen cells derived from mesopram-treated animals is significantly reduced compared to vehicle-treated controls. Amelioration of the clinical symptoms is also observed during chronic EAE in mesopram-treated SJL mice as well as in relapsing-remitting EAE in SWXJ mice using a therapeutic treatment regimen. These data demonstrate the anti-inflammatory activity of mesopram and provide a rationale for its clinical development.

Histone deacetylase inhibitors: a survey of recent patents

Histone deacetylase (HDAC) inhibitors have been the subject of an intense drug discovery effort in the pharmaceutical industry and in some academic institutions over the last few years. Although, at present, only a small number of compounds have progressed to human clinical trials, the prospect of finding safe compounds useful in therapy, particularly in cancer and inflammatory processes, is still a strong motivating factor for further research efforts. A patent literature review of small organic molecules as HDAC inhibitors is presented here, as many of the major pharmaceutical companies have shown a continued effort in the field [1]. This paper provides an update on the patenting activity in 2004 – 2005 related to HDAC inhibitors.

Recent Advances in Medicinal Chemistry of Histone Deacetylase Inhibitors

Publisher Summary Histone deacetylases (HDACs) inhibitors induce histone hyperacetylation, reactivate suppressed genes and consequently, inhibit the cell cycle, activate differentiation programmes or induce apoptosis and several HDAC inhibitors of various structural families have now advanced into phase I and II clinical trials. Mammalian HDACs can be divided into three distinct classes. Class I deacetylases, HDACs 1, 2, 2, 8, share homology in their catalytic sites with molecular weights of 42–55 kDa. Class II deacetylases includes HDACs with molecular weights between 120–130 kDa. The third class of deacetylases is the conserved Sir2 family of proteins which are dependent on NAD + for activity whereas Class I and II HDACs operate by zinc-dependent mechanisms. HDAC inhibitors bear great potential as new drugs because of their ability to modulate transcription, and are endowed with cytodifferentiating, antiproliferative and apoptogenic properties. Furthermore the anticancer activity of HDAC inhibitors may be mediated in part by the inhibition of angiogenesis, since it was shown recently that TSA specifically inhibited hypoxia-induced angiogenesis by reducing the expression of genes required for angiogenesis. Several structural classes of compounds have been described as HDAC inhibitors. The most important of these compound classes are short-chain fatty acids, hydroxamic acids, benzamides, and cyclic tetrapeptides.

Synthesis of 4-arylpyridines and substituted β-carbolines via 1,4-Grignard-addition to pyridinecarboxamides

Abstract 2,5-Pyridinedicarboxamides 1 and 2 , 5-bromo-3-pyridinecarboxamide 7 and 3-hydroxy-2,5-pyridinedicarboxamide 9 undergo 1,4-addition with Grignard reagents to give the 2,4,5-or 3,4,5-and 2,3,4,5-substituted pyridines 3–6, 8 and 10 after oxidation with NCS or oxygen. After selective transformation of amides 5 and 8 to carbamates 17 and 19 , a modified intramolecular Goldberg amide arylation furnishes the β -carbolines 22 and 24 in good yields.

Synthesis of ENT-17-(prop-1-ynyl-17β-hydroxy-11β-(4-(N,N-dimethylamino) -phenyl)-4,9-estradien-3-one, the antipode of RU — 38 486

The title compound was synthesized and tested for its biological activities. It showed neither antiprogesterone nor antiglucocorticoid properties.

Synthesis of 14β-H antiprogestins

Abstract An efficient approach to 14β-H antiprogestins is described. The key step of the synthesis is a cleavage of 17-silyl dienol ethers 7 respectively 12, which are generated from the corresponding Δ 14 -17-ketones, with hydrogen fluoride-pyridine complex. This method gave access to 14β-H analogs of the 11β,19-bridged series (type A) as well as of the 10β-H,11β-aryl series (type B).

11β-Aryl Steroids in the Androstene Series. The Role of the 11β-Region in Steroid Progesterone Receptor Interaction

Abstract The syntheses of 11β-arylandrost-4-en-3-one 24 and the corresponding 9β,19-cyclo derivative 8 are described. Steric interaction between C-19 and the aryl residue effects conformational changes of the steroid ring system that result in reduced affinity for the progesterone receptor. The conformation of 11β-arylandrostenes is discussed in comparison with known antiprogestational steroids.

Synthesis of 11α-methyl-11β-(arylethynyl)substituted steroids of the estrane series

The synthesis of 11α-methyl-11β-(arylethynyl) substituted 19-norsteroids of 13, 14, and 15 is described. The preparation of these compounds opens for the first time an approach to 11-disubstituted antiprogestins.

Synthesis of oxygen-bridged antigestagens

Abstract A synthetic access to 10,11β-(oxy-1,2-phenylene)-steroids 13 is described. Key steps are the S N 2′ type introduction of suitably ortho substituted arenes into vinyl epoxide 4 , and ring closure by an acid catalysed intramolecular epoxide opening with the corresponding phenol. The resulting oxygen bridged steroids 13 are transformed into pharmacologically relevant progesterone antagonists 19a–c and 20 .

Synthesis of 11β-(alkynyl)substituted 19-norsteroids

Abstract A new access to 11β-(alkynyl)estranes I is described. The synthesis of key intermediate 11β-ethynylestr-4-ene-3,17-dione 8 can be achieved by stereoselective thermodynamically controlled formation of 11β-aldehyde 1 , its conversion to vinyl bromide 7 by Wittig reaction and subsequent dehydrobromination. Broad variation of the acetylenic 11β-substitution is possible by nucleophilic substitution as well as transition metal mediated coupling reactions.