- INHIBITORS OF PLASMA KALLIKREIN AND USES THEREOF
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The present invention provides compounds and compositions thereof which are useful as inhibitors of plasma kallikrein and which exhibit desirable characteristics for the same.
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- Inhibition of the Cysteine Protease Human Cathepsin L by Triazine Nitriles: Amide???Heteroarene π-Stacking Interactions and Chalcogen Bonding in the S3 Pocket
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We report an extensive “heteroarene scan” of triazine nitrile ligands of the cysteine protease human cathepsin L (hCatL) to investigate π-stacking on the peptide amide bond Gly67–Gly68 at the entrance of the S3 pocket. This heteroarene???peptide bond stacking was supported by a co-crystal structure of an imidazopyridine ligand with hCatL. Inhibitory constants (Ki) are strongly influenced by the diverse nature of the heterocycles and specific interactions with the local environment of the S3 pocket. Binding affinities vary by three orders of magnitude. All heteroaromatic ligands feature enhanced binding by comparison with hydrocarbon analogues. Predicted energetic contributions from the orientation of the local dipole moments of heteroarene and peptide bond could not be confirmed. Binding of benzothienyl (Ki=4 nm) and benzothiazolyl (Ki=17 nm) ligands was enhanced by intermolecular C?S???O=C interactions (chalcogen bonding) with the backbone C=O of Asn66 in the S3 pocket. The ligands were also tested for the related enzyme rhodesain.
- Giroud, Maude,Ivkovic, Jakov,Martignoni, Mara,Fleuti, Marianne,Trapp, Nils,Haap, Wolfgang,Kuglstatter, Andreas,Benz, J?rg,Kuhn, Bernd,Schirmeister, Tanja,Diederich, Fran?ois
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supporting information
p. 257 - 270
(2017/02/15)
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- Discovery and structural optimization of 4-(4-(benzyloxy)phenyl)-3,4-dihydropyrimidin-2(1H)-ones as RORc inverse agonists
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Aim: Retinoic acid receptor-related orphan nuclear receptors (RORs) are orphan nuclear receptors that show constitutive activity in the absence of ligands. Among 3 subtypes of RORs, RORc is a promising therapeutic target for the treatment of Th17-mediated autoimmune diseases. Here, we report novel RORc inverse agonists discovered through structure-based drug design. Methods: Based on the structure of compound 8, a previously described agonist of RORa, a series of 4-(4-(benzyloxy)phenyl)-3,4-dihydropyrimidin-2(1H)-one derivatives were designed and synthesized. The interaction between the compounds and RORc was detected at molecular level using AlphaScreen assay. The compounds were further examined in 293T cells transfected with RORc and luciferase reporter gene. Thermal stability shift assay was used to evaluate the effects of the compounds on protein stability. Results: A total of 27 derivatives were designed and synthesized. Among them, the compound 22b was identified as the most potent RORc inverse agonist. Its IC50 values were 2.39 μmol/L in AlphaScreen assay, and 0.82 μmol/L in inhibition of the cell-based luciferase reporter activity. Furthermore, the compound 22b displayed a 120-fold selectivity for RORc over other nuclear receptors. Moreover, a molecular docking study showed that the structure-activity relationship was consistent with the binding mode of compound 22b in RORc. Conclusion: 4-(4-(Benzyloxy)phenyl)-3,4-dihydropyrimidin-2(1H)-one derivatives are promising candidates for the treatment of Th17-mediated autoimmune diseases, such as rheumatoid arthritis, psoriasis, and multiple sclerosis.
- Wu, Xi-Shan,Wang, Rui,Xing, Yan-Li,Xue, Xiao-Qian,Zhang, Yan,Lu, Yong-Zhi,Song, Yu,Luo, Xiao-Yu,Wu, Chun,Zhou, Yu-Lai,Jiang, Jian-Qin,Xu, Yong
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p. 1516 - 1524
(2016/11/11)
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- BENZOXAZINE DERIVATIVES AS GLYCINE TRANSPORT INHIBITORS
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The present invention relates to benzoxazinone derivatives, processes for their preparation, pharmaceutical compositions and medicaments containing them and to their use in treating disorders mediated by Gly T1, including neurological and neuropsychiatric disorders, in particular psychoses, dementia or attention deficit disorder.
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Page/Page column 74-75
(2011/04/14)
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- BENZOXAZINONE DERIVATIVES FOR THE TREATMENT OF GLYTL MEDIATED DISORDERS
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The present invention relates to benzoxazinone derivatives, processes for their preparation, pharmaceutical compositions and medicaments containing them and to their use in treating disorders mediated by GlyT1, including neurological and neuropsychiatric disorders, in particular psychoses, dementia or attention deficit disorder.
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Page/Page column 102; 103
(2011/02/24)
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- METHYL SULFANYL PYRMIDMES USEFUL AS ANTIINFLAMMATORIES, ANALGESICS, AND ANTIEPILEPTICS
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The present invention relates to pyrimidine derivatives of Formula (Ia) and (Ib) (including tautomers, isomers, prodrugs, and pharmaceutically acceptable salts thereof). Said compounds are useful in the treatment of pain (such as neuropathic pain), inflammation, and epilepsy (by acting as anticonvulsants). Methods of medical treatment making use of said compounds, as well as additional compounds of Formula (IIa) and (IIb), are also disclosed.
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Page/Page column 111
(2010/12/18)
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- Benzooxazole and benzothiazole antagonists of gonadotropin releasing hormone receptor
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The present invention relates to Gonadotropin Releasing Hormone (GnRH, also known as Luteinizing Hormone Releasing Hormone) receptor antagonists.
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Page/Page column 37
(2008/06/13)
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- Piperazinylimidazopyridine and piperazinyltriazolopyridine antagonists of gonadotropin releasing hormone receptor
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The present invention relates to Gonadotropin Releasing Hormone (GnRH, also known as Luteinizing Hormone Releasing Hormone) receptor antagonists.
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Page/Page column 39
(2008/06/13)
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- Processes for preparing gonadotropin releasing hormone receptor antagonists
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The present invention relates to methods of making Gonadotropin Releasing Hormone (“GnRH”) (also known as Leutinizing Hormone Releasing Hormone) receptor antagonists.
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Page/Page column 18
(2008/06/13)
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- Methods for preparing 5- and 6-benzyl-functionalized quinoxalines
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The present invention pertains to methods for preparing 5- and 6-benzyl functionalized quinoxalines. In a first embodiment, the method comprises contacting an aqueous suspension of a 5- and 6-halomethyl quinoxaline with a water-soluble nucleophile. In a second embodiment, the method comprises contacting a 5- and 6-halomethyl quinoxaline with an organic solvent-soluble nucleophile in an inert polar organic solvent. In a third embodiment, the method comprises contacting a 5- and 6-halomethyl quinoxaline in an organic solvent with an aqueous solution of a water-soluble nucleophile in the presence of a phase transfer catalyst.
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- Studies on New Acidic Azoles as Glucose-Lowering Agents in Obese, Diabetic db/db Mice
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Bioisosteric substitution was used as a tool to generate several new structural alternatives to the thiazolidine-2,4-dione and tetrazole heterocycles as potential antidiabetic agents.Among the initial leads that emerged from this strategy, a family of aci
- Kees, Kenneth L.,Caggiano, Thomas J.,Steiner, Kurt E.,Fitzgerald, John J.,Kates, Michael J.,et al.
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p. 617 - 628
(2007/10/02)
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- Heterocyclic thiazole derivatives and pharmaceutical compositions comprising said derivatives
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The invention concerns a thiazole of the formula I, STR1 wherein Q1 is an optionally substituted 6-membered monocyclic or 10-membered bicyclic heterocyclic moiety containing one or two nitrogen atoms; X is oxy, thio, sulphinyl, sulphonyl or imino; Ar is phenylene which may optionally bear one or two substituents, or Ar is an optionally substituted 6-membered heterocyclene moiety continuing up to three nitrogen atoms; R1 is hydrogen, (1-6C)alkyl, (2-6C)alkenyl, (2-6C)alkynyl or substituted (1-4C)alkyl; R2 is hydrogen, (1-6C)alkyl, (3-6C)alkenyl, (3-6C)alkynyl or substituted (1-4C)alkyl or R2 is optionally substituted benzoyl; and Q2 is optionally substituted thiazolyl; or a pharmaceutically-acceptable salt thereof. The invention also concerns processes for the manufacture of a thiazole of the formula I and pharmaceutical compositions containing said thiazole.
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- HETEROCYCLES FOR USE AS INHIBITORS OF LEUKOTRIENES
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The invention concerns a heterocycle of the formula I wherein Q is an optionally substituted 6-membered monocyclic or 10-membered bicyclic heterocyclic moiety containing one or two nitrogen atoms; A is (1-6C)alkylene, (3-6C)alkenylene, (3-6C)alkynylene or cyclo(3-6C)alkylene; X is oxy, thio, sulphinyl, sulphonyl or imino; Ar is phenylene which may optionally bear one or two substituents or Ar is an optionally substituted 6-membered heterocyclene moiety containing up to three nitrogen atoms; R 1 is hydrogen, (1-6C)alkyl, (3-6C)alkenyl, (3-6C)alkynyl, cyano-(1-4C)alkyl or (2-4C)alkanoyl, or optionally substituted benzoyl; and R 2 and R 3 together form a group of the formula --A 2 --X 2 --A 3 -- which, together with the carbon atom to which A 2 and A 3 are attached, defines a ring having 4 to 7 ring atoms, wherein A 2 and A 3, which may be the same or different, each is (1-4C)alkylene and X 2 is oxy, thio, sulphinyl, sulphonyl or imino; or a pharmaceutically-acceptable salt thereof. The compounds of the invention are inhibitors of the enzyme 5-lipoxygenase.
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- Heterocyclic derivatives
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The invention concerns a thiazole of the formula I, wherein Q1 is an optionally substituted 6-membered monocyclic or 10-membered bicyclic heterocyclic moiety containing one or two nitrogen atoms;, X is oxy, thio, sulphinyl, sulphonyl or imino;, Ar is phenylene which may optionally bear one or two substituents, or Ar is an optionally substituted 6-membered heterocyclene moiety contining up to three nitrogen atoms;, R1 is hydrogen, (1-6C)alkyl, (2-6C)alkenyl, (2-6C)alkynyl or substituted (1-4C)alkyl;, R2 is hydrogen, (1-6C)alkyl, (3-6C)alkenyl, (3-6C)alkynyl or substituted (1-4C)alkyl or R2 is optionally substituted benzoyl; and, Q2 is optionally substituted thiazolyl;, or a pharmaceutically-acceptable salt thereof. The invention also concerns processes for the manufacture of a thiazole of the formula I and pharmaceutical compositions containing said thiazole.
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