- HYDANTOIN AND THIOHYDANTOIN DERIVATIVES AS ANTIVIRAL DRUGS
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The present invention relates to a compound of the following formula (I), or a salt, solvate, tautomer, enantiomer, diastereoisomer or racemic mixture thereof: as well as its use as a drug, notably in the treatment of hepatitis C, its preparation process, and the pharmaceutical compositions containing such a compound.
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Page/Page column 155-156
(2013/12/03)
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- Novel triazines as potent and selective phosphodiesterase 10A inhibitors
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The identification of highly potent and orally active triazines for the inhibition of PDE10A is reported. The new analogs exhibit low-nanomolar potency for PDE10A, demonstrate high selectivity against all other members of the PDE family, and show desired drug-like properties. Employing structure-based drug design approaches, we investigated the selectivity of PDE10A inhibitors against other known PDE isoforms, by methodically exploring the various sub-regions of the PDE10A ligand binding pocket. A systematic assessment of the ADME and pharmacokinetic properties of the newly synthesized compounds has led to the design of drug-like candidates with good brain permeability and desirable drug kinetics (t1/2, bioavailability, clearance). Compound 66 was highly potent for PDE10A (IC50 = 1.4 nM), demonstrated high selectivity (>200×) for the other PDEs, and was efficacious in animal models of psychoses; reversal of MK-801 induced hyperactivity (MED = 0.1 mg/kg) and conditioned avoidance responding (CAR; ID50 = 0.2 mg/kg).
- Malamas, Michael S.,Ni, Yike,Erdei, James,Fan, Kristi Yi,Parris, Kevin,Marquis, Karen L.,Grauer, Steve,Brennan, Julie,Navarra, Rachel,Graf, Radka,Harrison, Boyd L.,Robichaud, Albert,Pangalos, Menelas N.,Brandon, Nicholas J.,Stange, Hans,Schindler, Rudolf,Lankau, Hans-Joachim,Grunwald, Christian,Langen, Barbara,Egerland, Ute,Hage, Thorsten,Kronbach, Thomas,Hoefgen, Norbert
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p. 5876 - 5884,9
(2020/07/30)
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- Highly potent, selective, and orally active phosphodiesterase 10A inhibitors
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The identification of highly potent and orally active phenylpyrazines for the inhibition of PDE10A is reported. The new analogues exhibit subnanomolar potency for PDE10A, demonstrate high selectivity against all other members of the PDE family, and show desired druglike properties. Employing structure-based drug design approaches, we methodically explored two key regions of the binding pocket of the PDE10A enzyme to alter the planarity of the parent compound 1 and optimize its affinity for PDE10A. Bulky substituents at the C9 position led to elimination of the mutagenicity of 1, while a crucial hydrogen bond interaction with Glu716 markedly enhanced its potency and selectivity. A systematic assessment of the ADME and PK properties of the new analogues led to druglike development candidates. One of the more potent compounds, 96, displayed an IC50 for PDE10A of 0.7 nM and was active in predictive antipsychotic animal models.
- Malamas, Michael S.,Ni, Yike,Erdei, James,Stange, Hans,Schindler, Rudolf,Lankau, Hans-Joachim,Grunwald, Christian,Fan, Kristi Yi,Parris, Kevin,Langen, Barbara,Egerland, Ute,Hage, Thorsten,Marquis, Karen L.,Grauer, Steve,Brennan, Julie,Navarra, Rachel,Graf, Radka,Harrison, Boyd L.,Robichaud, Albert,Kronbach, Thomas,Pangalos, Menelas N.,Hoefgen, Norbert,Brandon, Nicholas J.
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p. 7621 - 7638
(2012/01/05)
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- IMIDAZO[5,1-C][1,2,4]BENZOTRIAZINE DERIVATIVES AS INHIBITORS OF PHOSPHODIESTERASES
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The invention relates to imidazo[5,1-c][1,2,4]benzotriazine derivatives of formula I: which are inhibitors of phosphodiesterase 2 or 10 useful in treating central nervous system diseases such as psychosis and also in treating, for example, obesity, type 2 diabetes, metabolic syndrome, glucose intolerance, and pain.
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Page/Page column 32
(2010/06/11)
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- ARYL AND HETEROARYL FUSED IMIDAZO[1,5-a]PYRAZINES AS INHIBITORS OF PHOSPHODIESTERASE 10
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The invention relates to imidazo[1,5-a]pyrazine derivatives, to processes for preparing them, to pharmaceutical preparations which comprise these compounds and to the pharmaceutical use of these compounds, which are inhibitors of phosphodiesterase 10 (PDE10), as active compounds for treating central nervous system diseases of mammals, including humans.
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Page/Page column 27
(2009/06/27)
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- COMPOUNDS WHICH HAVE ACTIVITY AT M1 RECEPTOR AND THEIR USES IN MEDICINE
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Compounds which have activity at M1 receptor and their uses in medicine Compounds of formula (I) and salts and solvates are provided: wherein R4 is fluoro, R5 is selected from hydrogen, halogen, cyano, C1-6alkyl
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Page/Page column 45
(2010/11/26)
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- The Effect of Fluorine Substitution on the Metabolism and Antimalarial Activity of Amodiaquine
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Amodiaquine (AQ) (2) is a 4-aminoquinoline antimalarial which causes adverse side effects such as agranulocytosis and liver damage.The observed drug toxicity is believed to be related to the formation of an electrophilic metabolite, amodiaquine imine (AQQI), which can bind to cellular macro-molecules and initiate hypersensitivity reactions. 5'-Fluoroamodiaquine (5'-FAQ, 3), 5',6'-difluoroamodiaquine (5',6'-DIFAQ, 4), 2',6'-difluoroamodiaquine (2',6'-DIFAQ, 5), 2',5',6'-trifluoroamodiaquine (2',5',6'-TRIFAQ, 6) and 4'-dehydroxy-4'-fluoroamodiaquine (4'-deOH-4'-FAQ, 7) have been synthesized to assess the effect of fluorine substitution on the oxidation potential, metabolism, and in vitro antimalarial activity of amodiaquine.The oxidation potentials were measured by cyclic voltammetry, and it was observed that substitution at the 2',6'- and 4'-positions (2',6'-DIFAQ and 4'-deOH'4'-FAQ) produced analogues with significantly higher oxidation potentials than the parent drug.Fluorine substitution at the 2',6'-positions and 4'-position also produced analogues that were more resistant to bioactivation.Thus 2',6'-DIFAQ and 4'-deOH-4'-FAQ produced thioether conjugates corresponding to 2.17percent (SD: +/-0.27percent) and 0percent of the dose compared with 11.87percent (SD: +/-1.31percent) of the dose for amodiaquine.In general the fluorinated analogues had similar in vitro antimalarial activity to amodiaquine against the chloroquine resistant K1 strain of Plasmodium falciparum and the chloroquine sensitive T9-96 strain of P. falciparum with the notable exception of 2',5',6'-TRIFAQ (6).The data presented indicate that fluorine substitution at the 2',6'-positions and replacement of the 4'-hydroxyl of amodiaquine with fluorine produces analogues ( 5 and 7) that maintain antimalarial efficacy in vitro and are more resistant to oxidation and hence less likely to form toxic quinone imine metabolites.
- O'Neill, Paul M.,Harrison, Anthony C.,Storr, Richard C.,Hawley, Shaun R.,Ward, Stephen A.,Park, B. Kevin
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p. 1362 - 1370
(2007/10/02)
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- The effect of fluorine substitution on the physicochemical properties and the analgesic activity of paracetamol
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The physicochemical properties and analgesic action of six fluorinated analogues of 4-hydroxyacetanilide (paracetamol) have been investigated. Fluorine substitution adjacent to the hydroxyl group increased lipophilicity and oxidation potential whilst substitution adjacent to the amide had little effect on lipophilicity but led to a greater increase in oxidation potential. Lack of coplanarity and conjugation of the amide group and aromatic ring was also apparent with the analogues that had fluorine in the 2 and 6 positions. Introduction of fluorine into the amide group of paracetamol increased the lipophilicity 4-fold and also increased the oxidation potential of paracetamol. ED50 values for analgesic activity in the phenylquinone-induced abdominal constriction test on male Swiss White mice showed that ring substitution by fluorine reduced activity, especially at the 2,6-positions. Introduction of fluorine into the amide group enhanced activity significantly. Correlation of the analgesic activity with the physicochemical properties indicated that conjugation (and planarity) of the amide group with the aromatic ring is essential for activity and that ease of oxidation may also be an important factor.
- Barnard,Storr,O'Neill,Park
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p. 736 - 744
(2007/10/02)
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