- 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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experimental part
p. 7621 - 7638
(2012/01/05)
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- NOVEL MEK INHIBITORS, USEFUL IN THE TREATMENT OF DISEASES
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The invention pertains to compound of Formula (I) wherein X, Y, Z, R1, R2, R3, R4, A and A' are as described hereinabove. Formula (I) and (II) compounds can be used in pharmaceutical compositions, useful for the treatment of diseases
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Page/Page column 49
(2011/05/05)
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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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- 1-ORTHOFLUOROPHENYL SUBSTITUTED 1, 2 , 5-THIAZOLIDINEDIONE DERIVATIVES AS PTP-AS INHIBITORS
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Compounds of the formula (I) are inhibitors of protein tyrosine phosphatases (PTPases) and, thus, may be employed for the treatment of conditions mediated by PTPase activity. The compounds of the present invention may also be employed as inhibitors of other enzymes characterized with a phosphotyrosine binding region such as the SH2 domain. Accordingly, the compounds of formula (I) may be employed for prevention and/or treatment of insulin resistance associated with obesity, glucose intolerance, diabetes mellitus, hypertension and ischemic diseases of the large and small blood vessels, conditions that accompany type-2 diabetes, including hyperlipidemia, hypertriglyceridemia, atherosclerosis, vascular restenosis, irritable bowel syndrome, pancreatitis, adipose cell tumors and carcinomas such as liposarcoma, dyslipidemia, and other disorders where insulin resistance is indicated. In addition, the compounds of the present invention may be employed to treat and/or prevent cancer, osteoporosis, neurodegenerative and infectious diseases, and diseases involving inflammation and the immune system.
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Page/Page column 70
(2010/11/27)
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- VANILLOID RECEPTOR LIGANDS AND THEIR USE IN TREATMENTS
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Pyrimidine ethers and compositions containing them, for the treatment of acute, inflammatory and neuropathic pain, dental pain, general headache, migraine, cluster headache, mixed-vascular and non-vascular syndromes, tension headache, general inflammation, arthritis, rheumatic diseases, osteoarthritis, inflammatory bowel disorders, inflammatory eye disorders, inflammatory or unstable bladder disorders, psoriasis, skin complaints with inflammatory components, chronic inflammatory conditions, inflammatory pain and associated hyperalgesia and allodynia, neuropathic pain and associated hyperalgesia and allodynia, diabetic neuropathy pain, causalgia, sympathetically maintained pain, deafferentation syndromes, asthma, epithelial tissue damage or dysfunction, herpes simplex, disturbances of visceral motility at respiratory, genitourinary, gastrointestinal or vascular regions, wounds, burns, allergic skin reactions, pruritus, vitiligo, general gastrointestinal disorders, gastric ulceration, duodenal ulcers, diarrhea, gastric lesions induced by necrotising agents, hair growth, vasomotor or allergic rhinitis, bronchial disorders or bladder disorders.
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Page/Page column 29
(2008/06/13)
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- VLA-4 INHIBITORS
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The present invention relates to a compound represented by the following formula (I): (wherein, W represents WA-A1 -WB - (in which, WA is substituted or unsubstituted aryl, etc., A1 is -NR1-, single bond, -C(O)-, etc., and WB is substituted or unsubstituted arylene, etc.), R is single bond, -NH-, -OCH2-, alkenylene, etc., X is -C(O) -CH2-, etc., and M is, for example, the following formula: (in which, R11, R12 and R13 each independently represents hydrogen, hydroxyl, amino, halogen, etc., R14 is hydrogen or lower alkyl, Y represents -CH2-O-, etc., Z is substituted or unsubstituted arylene, etc., A2 is single bond, etc, and R10 is hydroxyl or lower alkoxy)), or salt thereof; and a medicament containing the same. This compound or salt thereof selectively inhibits binding of cell adhesion molecules to VAL-4 and exhibits high bioavailability so that it is useful as a preventive and/or remedy for inflammatory diseases, autoimmune diseases, metastasis, bronchial asthma, rhinostenosis, diabetes, and the like.
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- Novel compounds
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The invention provides compounds of general formula (I) wherein Q, R, R2, R4, R5, R6, R7 and R8 are as defined in the specification, processes for their preparation, pharmaceutical compositions containing them and their use in therapy.
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- Chemical compounds
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Compound of formula (I) wherein: A is a bicyclic heteroaryl, optionally substituted with one or more substituents; B is linker group connecting group A to group D and comprising a 3 or 4 atom linker where each atom is independently selected from carbon, oxygen, nitrogen and sulphur and is optionally subsituted with one or more C1-6alkyl groups or two of such adjacent alkyl substituents may form a ring; C is aryl or a mono or bicyclic heteroaryl, each of which can be optionally substituted; D is an aryl or heteroaryl, both of which are optionally substituted R1is hydrogen, C1-5alkyl, C1-3alkanoyl or C1-3alkoxycarbonyl; R2to R5are each independently selected from hydrogen, C1-6alkyl, aryl and heteroaryl containing up to 2 heteroatoms chosen from oxygen, sulphur and nitrogen, the aryl and heteroaryl optionally substituted with C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C1-4alkoxy, C1-4alkanoyl, C1-6alkylamino, C1-4alkylC1-6alkyoxyl, C1-6alkylaminoC1-6alkyl, nitro, cyano, halogeno, trifluoromethyl, hydroxy, (CH2)pOH where p is 1 or 2, —CO2Ra, and —CONRaRb, where Raand Rbare independently selected from hydrogen and C1-6alkyl or two of R2to R5can be taken together to form a 3 to 7 membered ring; R6is an acidic functional group; r and s are each independently 0 or 1 with the proviso that r and s cannot both be 0; or a pharmaceutically acceptable salt or in vivo hydrolysable derivative thereof.
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- Synthesis and characterization of two improved NMR indicators for cytosolic Ca2+: 3FBAPTA and 35FBAPTA
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Fluorinated derivatives of the calcium-selective chelator BAPTA [1,2-bis(2-aminophenoxy)ethane-N,N,N′,N′-tetraacetic acid] are popular NMR probes for cytosolic calcium ion concentration. Two such derivatives were synthesized and evaluated, 3FBAPTA [1,2-bis(2-amino-3-fluorophenoxy)ethane-N,N,N′,N′-tetraacetic acid] and 35FBAPTA [1,2-bis(2-amino-3,5-difluorophenoxy)ethane-N,N,N′,N′-tetraacetic acid]. The dissociation constant ratios obtained at 37°C were K3FD/K5FD = 0.60 and K35FD/K5FD = 0.88; similar values were obtained at 25°C. Hence 3FBAPTA binds calcium ions more tightly than 5FBAPTA [1,2-bis(2-amino-5-fluorophenoxy)ethane-N,N,N′,N′-tetraacetic acid, the currently most frequently utilized indicator], while the doubly substituted derivative exhibits intermediate affinity. The dissociation rate constants for the calcium complexes measured at 37°C exhibit a similar trend, with k5-1 > k35-1 > k3-1. Both of the additional derivatives exhibit slow exchange kinetics, and should be superior fluorine NMR probes owing to the decreased T1 values and, in the case of 35FBAPTA, the presence of two calcium-sensitive fluorine nuclei which are measured simultaneously.
- Levy, Louis A.,Gabel, Scott A.,London, Robert E.
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p. 440 - 446
(2007/10/03)
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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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