- Design, synthesis, and biological evaluation of 3-[4-(2-hydroxyethyl) piperazin-l-yl]7-(6-methoxypyridin-3-yl)-l-(2-propoxyethyl)pyrido[3,4-b] pyrazin-2(lH)-one, a potent, orally active, brain penetrant inhibitor of phosphodiesterase 5 (PDE5)
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We recently described a novel series of aminopyridopyrazinones as PDE5 inhibitors. Efforts toward optimization of this series culminated in the identification of 3-[4-(2-hydroxyethyl)piperazin-l-yl]7-(6-methoxypyridin-3-yl)- l-(2-propoxyethyl)pyrido[3,4-è]pyrazin-2(l//)-one, which possessed an excellent potency and selectivity profile and demonstrated robust in vivo blood pressure lowering in a spontaneously hypertensive rat (SHR) model. Furthermore, this compound is brain penetrant and will be a useful agent for evaluating the therapeutic potential of central inhibition of PDE5. This compound has recently entered clinical trials.
- Hughes, Robert O.,Rogier, D. Joseph,Jacobsen, E. Jon,Walker, John K.,Maclnnes, Alan,Bond, Brian R.,Zhang, Lena L.,Yu, Ying,Zheng, Yi,Rumsey, Jeanne M.,Walgren, Jennie L.,Curtiss, Sandra W.,Fobian, Yvette M.,Heasley, Steven E.,Cubbage, Jerry W.,Moon, Joseph B.,Brown, David L.,Acker, Brad A.,Maddux, Todd M.,Tollefson, Mike B.,Mischke, Brent V.,Owen, Dafydd R.,Freskos, John N.,Molyneaux, John M.,Benson, Alan G.,Blevis-Ba, Rhadika M.
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Read Online
- A Ruthenium(II) Complex as a Luminescent Probe for DNA Mismatches and Abasic Sites
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[Ru(bpy)2(BNIQ)]2+ (BNIQ = Benzo[c][1,7]naphthyridine-1-isoquinoline), which incorporates the sterically expansive BNIQ ligand, is a highly selective luminescent probe for DNA mismatches and abasic sites, possessing a 500-fold higher binding affinity toward these destabilized regions relative to well-matched base pairs. As a result of this higher binding affinity, the complex exhibits an enhanced steady-state emission in the presence of DNA duplexes containing a single base mismatch or abasic site compared to fully well-matched DNA. Luminescence quenching experiments with Cu(phen)22+ and [Fe(CN)6]3- implicate binding of the complex to a mismatch from the minor groove via metalloinsertion. The emission response of the complex to different single base mismatches, binding preferentially to the more destabilized mismatches, is also consistent with binding by metalloinsertion. This work shows that high selectivity toward destabilized regions in duplex DNA can be achieved through the rational design of a complex with a sterically expansive aromatic ligand.
- Boynton, Adam N.,Marcélis, Lionel,McConnell, Anna J.,Barton, Jacqueline K.
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Read Online
- Carbon-11 and Fluorine-18 Radiolabeled Pyridopyrazinone Derivatives for Positron Emission Tomography (PET) Imaging of Phosphodiesterase-5 (PDE5)
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The cyclic guanosine monophosphate (cGMP) specific phosphodiesterase type 5 (PDE5) plays an important role in various pathologies including pulmonary arterial hypertension and cardiomyopathy. PDE5 represents an important therapeutic and/or prognostic targ
- Chekol, Rufael,Gheysens, Olivier,Ahamed, Muneer,Cleynhens, Jan,Pokreisz, Peter,Vanhoof, Greet,Janssens, Stefan,Verbruggen, Alfons,Bormans, Guy
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Read Online
- PYRIDOPYRIMIDINES AS HISTAMINE H4-RECEPTOR INHIBITORS
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The invention relates to compounds of formula (I) or pharmaceutically acceptable salts or solvates thereof, to pharmaceutical compositions comprising them and to their use in the treatment and/or prevention of diseases or disorders mediated by histamine H4 receptor.
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Page/Page column 32; 34-36
(2020/02/16)
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- SULFONYL-SUBSTITUTED BICYCLIC COMPOUND WHICH ACTS AS ROR INHIBITOR
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Provided is a sulfonyl-substituted bicyclic compound (A) which acts as a RORγ inhibitor, said compound has good RORγ inhibitory activity and is expected to be used for treating diseases mediated by a RORγ receptor in mammals.
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Paragraph 0376; 0377
(2020/08/16)
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- Discovery of Pyridopyrimidinones as Potent and Orally Active Dual Inhibitors of PI3K/mTOR
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The identification and lead optimization of a series of pyridopyrimidinone derivatives are described as a novel class of efficacious dual PI3K/mTOR inhibitors, resulting in the discovery of 31. Compound 31 exhibited high enzyme activity against PI3K and mTOR, potent suppression of Akt and p70s6k phosphorylation in cell assays, and good pharmacokinetic profile. Furthermore, compound 31 demonstrated in vivo efficacy in a PC-3M tumor xenograft model.
- Yu, Tao,Li, Ning,Wu, Chengde,Guan, Amy,Li, Yi,Peng, Zhengang,He, Miao,Li, Jie,Gong, Zhen,Huang, Lei,Gao, Bo,Hao, Dongling,Sun, Jikui,Pan, Yan,Shen, Liang,Chan, Chichung,Lu, Xiulian,Yuan, Hongyu,Li, Yongguo,Li, Jian,Chen, Shuhui
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supporting information
p. 256 - 261
(2018/03/21)
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- MACROCYCLIC INHIBITORS OF FLAVIVIRIDAE VIRUSES
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Provided are compounds of Formula I: and pharmaceutically acceptable salts and esters thereof. The compounds, compositions, and methods provided are useful for the treatment of virus infections, particularly hepatitis C infections.
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Paragraph 0563
(2017/08/01)
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- 4-(5-(2-(3,5-bis(trifluoromethyl)phenyl)-N,2-dimethylpropanamido)-4-(o-tolyl)pyridin-2-yl)-1-methyl-1-((phosphonooxy)methyl)piperazin-1-ium as a neurokinin receptor modulator
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Compounds and methods for the prevention and/or treatment of diseases which are pathophysiologically mediated by the neurokinin (NK1) receptor, based on 4-(5-(2-(3,5-bis(trifluoromethyl)phenyl)-N,2-dimethylpropanamido)-4-(o-tolyl)3yridine-2-yl)-1-methyl-1-((phosphonooxy)methyl)piperazin-1-ium and pharmaceutically acceptable salts thereof.
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Page/Page column 33
(2016/08/29)
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- Bicyclic heteroaromatic compounds as protein tyrosine kinase inhibitors
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A pharmaceutical formulation comprising the compound of formula
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Page/Page column 37
(2015/12/18)
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- SUBSTITUTED 4-PHENYL-PYRIDINES FOR TREATMENT OF NK-1 RECEPTOR RELATED DISEASES
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PROBLEM TO BE SOLVED: To provide new derivatives of 4-phenyl-pyridine compounds that are effective NK1 receptor antagonists, with enhanced physicochemical and/or biological properties, and methods for producing the 4-phenyl-pyridine compounds. SOLUTION: Disclosed are compounds, compositions and methods for the prevention and/or treatment of diseases which are pathophysiologically mediated by the neurokinin (NKj) receptor. The compounds have the general formula (I). COPYRIGHT: (C)2015,JPOandINPIT
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Paragraph 0164; 0165
(2018/10/31)
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- SMALL MOLECULE AGONISTS OF NEUROTENSIN RECEPTOR 1
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Provided herein are small molecule neurotensin receptor agonists, compositions comprising the compounds, and methods of using the compounds and compositions comprising the compounds.
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Paragraph 00478
(2016/04/26)
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- TRKA KINASE INHIBITORS, COMPOSITIONS AND METHODS THEREOF
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The present invention is directed to six membered heteroaryl benzamide compounds of formula (I), which are tropomyosin-related kinase (Trk) family protein kinase inhibitors, and hence are useful in the treatment of pain, inflammation, cancer, restenosis, atherosclerosis, psoriasis, thrombosis, a disease, disorder, injury, or malfunction relating to dysmyelination or demyelination or a disease or disorder associated with abnormal activities of nerve growth factor (NGF) receptor TrkA.
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Page/Page column 35
(2015/12/30)
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- MACROCYCLIC INHIBITORS OF FLAVIVIRIDAE VIRUSES
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Provided are compounds of Formula I: and pharmaceutically acceptable salts and esters thereof. The compounds, compositions, and methods provided are useful for the treatment of virus infections, particularly hepatitis C infections.
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Page/Page column 215
(2014/01/08)
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- Substituted 4-phenyl pyridines having anti-emetic effect
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Disclosed are compounds, compositions and methods for the prevention and/or treatment of diseases which are pathophysiologically mediated by the neurokinin (NK1) receptor. The compounds have the general formula (I):
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Page/Page column 28; 29
(2013/05/08)
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- An efficient synthesis of 2-amino-5-chloro-3-pyridinecarbox-aldehyde and 5-amino-2-chloro-4-pyridinecarboxaldehyde
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Efficient synthetic routes to the title compounds 2-amino-5-chloro-3- pyridinecarboxaldehyde (1a) and 5-amino-2-chloro-4-pyridinecarboxaldehyde (1b) are reported. Both compounds are important substrates in the synthesis of naph-thyridine derivatives. Copyright by Walter de Gruyter Berlin Boston.
- Hou, Chuan-Jin,Guo, Wei-Lei,Liu, Xiao-Ning,Yang, Da-Wei
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experimental part
p. 21 - 23
(2011/10/02)
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- Discovery of potent, balanced and orally active dual NK1/NK3 receptor ligands
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During a program directed at selective NK1 receptor antagonists, we serendipitously discovered an NK1 receptor ligand with additional affinity for the NK3 receptor. Recognising an opportunity for a drug discovery program aiming for dual NK1/NK3 receptor antagonists, we prepared a series of analogues from a novel, versatile building block. From this series emerged compounds with high and balanced affinities for the NK1 and the NK3 receptors. Typical representatives of this series were active in the gerbil foot tapping assay after oral administration.
- Peters, Jens-Uwe,Hoffmann, Torsten,Schnider, Patrick,Stadler, Heinz,Koblet, Andreas,Alker, André,Poli, Sonia Maria,Ballard, Theresa M.,Spooren, Will,Steward, Lucinda,Sleight, Andrew J.
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scheme or table
p. 3405 - 3408
(2010/07/16)
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- AZAINDOLE DERIVATIVES AS CFTR MODULATORS
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The present invention relates to modulators of ATP-Binding Cassette (“ABC”) transporters or fragments thereof, including Cystic Fibrosis Transmembrane Conductance Regulator (“CFTR”), compositions thereof, and methods therewith. The present invention also relates to methods of treating ABC transporter mediated diseases using such modulators.
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Page/Page column 24
(2009/10/17)
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- Rearrangement of N,N-di-tert-butoxycarbonylpyridin-4-amines and formation of polyfunctional pyridines
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(Chemical Equation Presented) N,N-Di-tert-butoxycarbonylpyridin-4-amines were found to be rearranged to tert-butyl 4-(tert-butoxycarbonylamino) nicotinates by treatment with LDA in THF.
- Liu, Yahua,Ding, Qiang,Wu, Xu
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p. 6025 - 6028
(2008/12/21)
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- AZAQUINOLONE BASED COMPOUNDS EXHIBITING PROLYL HYDROXYLASE INHIBITORY ACTIVITY, COMPOSITIONS, AND USES THEREOF
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Compounds of Formula (I) are useful as inhibitors of HIF prolyl hydroxylases where the definitions of the variables are provided herein.
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- QUINOLONES AND AZAQUINOLONES THAT INHIBIT PROLYL HYDROXYLASE
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Compounds of Formula I are useful inhibitors of HIF prolyl hydroxylases. Compounds of Formula I have the following structure: where the definitions of the variables are provided herein.
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Page/Page column 57
(2008/12/08)
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- HETEROCYCLIC HYDRAZIDE COMPOUND AND PESTICIDAL USE OF THE SAME
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A hydrazide compound represented by the formula (I), an N-oxide thereof or suitable salt thereof: has excellent pesticidal activity.
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Page/Page column 403-404
(2008/12/08)
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- Pyridine [3,4-b] Pyrazinones
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Compounds and pharmaceutically acceptable salts of the compounds are disclosed, wherein the compounds have the structure of Formula I: wherein R2, R6A, R6B and R8 are as defined in the specification. Corresponding pharmaceutical compositions, methods of treatment, synthetic methods, and intermediates are also disclosed.
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Page/Page column 29; 31; 34
(2008/06/13)
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- PYRROLOPYRIDINE-2-CARBOXYLIC ACID AMIDES
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Compounds represented by Formula (I) or pharmaceutically acceptable salts thereof, are useful in the prophylactic or therapeutic treatment of diabetes, hyperglycemia, hypercholesterolemia, hyperinsulinemia, hyperlipidemia, hypertension, atherosclerosis or tissue ischemia e.g. myocardial ischemia, and as cardioprotectants.
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Page/Page column 22
(2008/06/13)
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- PYRIDINE [3 , 4-B] PYRAZINONE COMPOUNDS AS PDE-5 INHIBITORS
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Compounds, tautomers of the compounds, and pharmaceutically acceptable salts of the compounds or tautomers are disclosed, wherein the compounds have the structure of Formula (I), wherein R22, X6, Y6, R6, and R8 are as defined in the specification. Corresponding pharmaceutical compositions, methods of treatment, synthetic methods, and intermediates are also disclosed.
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Page/Page column 54; 58
(2010/11/25)
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- PYRIDINE [3,4-B] PYRAZINONES
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Compounds, tautomers of the compounds, and pharmaceutically acceptable salts of the compounds or tautomers are disclosed, wherein the compounds have the structure of Formula I: wherein R2, X6, Y6, R6, and R8 are as defined in the specification. Corresponding pharmaceutical compositions, methods of treatment, synthetic methods, and intermediates are also disclosed.
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Page/Page column 55; 59-60
(2010/11/25)
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- QUINAZOLINONE DERIVATIVES AND THEIR USE AS B-RAF INHIBITORS
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The invention relates to chemical compounds of the formula (I): or pharmaceutically acceptable salts thereof, which possess B Raf inhibitory activity and are accordingly useful for their anti cancer activity and thus in methods of treatment of the human or animal body. The invention also relates to processes for the manufacture of said chemical compounds, to pharmaceutical compositions containing them and to their use in the manufacture of medicaments of use in the production of an anti-cancer effect in a warm blooded animal such as man.
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Page/Page column 74
(2008/06/13)
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- PYRIDO [3,4-D] PYRIMIDINE DERIVATIVES AS MATRIX METALLOPROTEINASE-13 INHIBITORS
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This invention relates to a pyrido[3,4-d]pyrimidine derivative of Formula (I), or a pharmaceutically acceptable salt thereof, wherein R, L', L2, V, L3, and R2 are as defined in the specification, that inhibits a matrix metalloproteinase-13 enzyme and thus is useful for treating diseases resulting from MMP-13 mediated tissue breakdown such as osteoarthritis, rheumatoid arthritis, cartilage damage, psoriatic arthritis, ankylosing spondylitis, heart failure, atherosclerosis, inflammatory bowel disease, multiple sclerosis, age-related macular degeneration, chronic obstructive pulmonary disease, asthma, periodontal diseases, psoriasis, cancer, and osteoporosis.
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Page/Page column 122
(2010/02/11)
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- Anilinoquinazolines as protein tyrosine kinase inhibitors
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Heteroaromatic compounds are described, methods for their preparation, pharmaceutical compositions containing them, methods of use, and their use in medicines. In particular, the invention relates to quinazoline and pyridopyrimidine derivatives which exhibit protein tyrosine kinase inhibition.
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Page/Page column 73
(2008/06/13)
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- Anilinoquinazaolines as protein tyrosine kianse inhibitors
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Heteroaromatic compounds are described, methods for their preparation, pharmaceutical compositions containing them, methods of use, and their use in medicines. In particular, the invention relates to quinazoline and pyridopyrimidine derivatives which exhibit protein tyrosine kinase inhibition.
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Page/Page column 45
(2008/06/13)
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- SUBSTITUTED-3-CYANO-[1.7],[1.5], AND [1.8]-NAPHTHYRIDINE INHIBITORS OF TYROSINE KINASES
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This invention provides compounds of formula (I) having structure (a) wherein A'' is a diavalent moiety selected from the group (a, b, c) which are useful as inhibitors of protein tyrosine kinase.
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- PYRROLOPYRIDINE-2-CARBOXYLIC ACID AMIDE INHIBITORS OF GLYCOGEN PHOSHORYLASE
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Compounds represented by Formula (I): or pharmaceutically acceptable salts thereof, are inhibitors of glycogen phosphorylase and are useful in the prophylactic or therapeutic treatment of diabetes, hyperglycemia, hypercholesterolemia, hyperinsulinemia, hyperlipidemia, hypertension, atherosclerosis or tissue ischemia e.g. myocardial ischemia, and as cardioprotectants.
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- BIARYL COMPOUNDS HAVING ANTI-INFECTIVE ACTIVITY
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Aromatic compounds exemplified by exhibit antimicrobial activity.
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Page/Page column 26
(2008/06/13)
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- Azaindole derivatives and their use as therapeutic agents
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The present invention relates to compounds of the formula (I): wherein: Het represents a heterocyclic residue selected from: where the dotted line in (b) represents an optional double bond; A completes a fused pyridine ring; and B completes a fused benzene or pyridine ring. The compounds are of particular use in the treatment or prevention of depression, anxiety, pain, inflammation, migaine, emesis or postherpetic neuralgia.
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- Indazolylamino quinazolines and pyridopyrimidines as inhibitors of the EGFr and c-erbB-2
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Described herein is the design and synthesis of indazolylaminopyridopyrimidines and quinazolines as inhibitors of the class 1 tyrosine kinase receptor family. Data is presented for N4-(1-benzyl-1H-indazol-5-yl)-N6,N6- dime
- Cockerill, Stuart,Stubberfield, Colin,Stables, Jeremy,Carter, Malcolm,Guntrip, Stephen,Smith, Kathryn,McKeown, Steve,Shaw, Robert,Topley, Peter,Thomsen, Lindy,Affleck, Karen,Jowett, Amanda,Hayes, David,Willson, Malcolm,Woollard, Patrick,Spalding, David
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p. 1401 - 1405
(2007/10/03)
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- 2-Aryl indole NK1 receptor antagonists: Optimisation of indole substitution
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The synthesis and biological evaluation of a series of 2-aryl indoles with high affinity for the human neurokinin-1 (hNK1) receptor are reported, concentrating on optimisation of the indole substitution.
- Cooper, Laura C.,Chicchi, Gary G.,Dinnell, Kevin,Elliott, Jason M.,Hollingworth, Gregory J.,Kurtz, Marc M.,Locker, Karen L.,Morrison, Denise,Shaw, Duncan E.,Tsao, Kwei-Lan,Watt, Alan P.,Williams, Angela R.,Swain, Christopher J.
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p. 1233 - 1236
(2007/10/03)
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- 4,4-disubstitued-1,4-dihydro-2H-3,1-benzoxazin-2-ones useful as HIV reverse transcriptase inhibitors and intermediates and processes for making the same
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The present invention relates to benzoxazinones of formula I: STR1 or stereoisomeric forms or mixtures, or pharmaceutically acceptable salt forms thereof, which are useful as inhibitors of HIV reverse transcriptase, and to pharmaceutical compositions and diagnostic kits comprising the same, methods of using the same for treating viral infection or as an assay standard or reagent, and intermediates and processes for making the same.
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- Synthesis of 6-substituted pyrido[3,4-d]pyrimidin-4(3H)-ones via directed lithiation of 2-substituted 5-aminopyridine derivatives
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Directed lithiation of Boc or pivaloyl derivatives of 2-substituted 5-aminopyridines with BuLi-TMEDA in diethyl ether at -10°C gave 4-lithio derivatives which were quenched with CO2 to give the analogous C-4 carboxylic acids. Hydrolysis of the protecting groups with either TFA or aqueous KOH gave 2-substituted 5-aminopyridine-4-carboxylic acids which were converted to 6-substituted pyrido[3,4-d]pyrimidin-4(3H)-ones by reaction with formamide or, more optimally, formamidine acetate. Boc protected aminopyridines provided the best overall results, with synthesis of these derivatives best achieved by direct reaction of the aminopyridine with di-tert-butyl dicarbonate in the absence of added base.
- Rewcastle, Gordon W.,Denny, William A.,Winters, R. Thomas,Colbry, Norman L.,Showalter, H. D. Hollis
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p. 2221 - 2226
(2007/10/03)
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