- COMPOUNDS TARGETING RNA-BINDING PROTEINS OR RNA-MODIFYING PROTEINS
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The invention relates to a compound represented by Formula (I): or a pharmaceutically acceptable salt thereof, compositions comprising the same and methods of preparing and using the same. The variables are described herein.
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- POTENT HUMAN NEURONAL NITRIC OXIDE SYNTHASE INHIBITORS
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Disclosed are 2-aminopyridine derivative compounds for use as inhibitors of nitric oxide synthase (NOS). In particular, the field of the invention relates to 2-aminopyridine derivative compounds for use as inhibitors of neuronal nitric oxide synthase (nNOS), which are formulated as pharmaceutical compositions for treating diseases and disorders associated with nNOS such as Alzheimer's, Parkinson's, and Huntington's diseases, and amytrophic lateral sclerosis, cerebral palsy, stroke/ischemic brain damage, and migraine headaches.
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Paragraph 00357; 00358
(2021/09/04)
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- TRI-SUBSTITUTED HETEROARYL DERIVATIVES AS SRC HOMOLOGY-2 PHOSPHATASE INHIBITORS
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The present disclosure provides certain tri-substituted heteroaryl derivatives that are Src Homology-2 phosphatase (SHP2) inhibitors and are therefore useful for the treatment of diseases treatable by inhibition of SHP2. Also provided are pharmaceutical compositions containing such compounds and processes for preparing such compounds.
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Page/Page column 123
(2020/04/25)
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- BENZIMIDAZOLE-LINKED INDOLE COMPOUND ACTING AS NOVEL DIVALENT IAP ANTAGONIST
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The present invention discloses a benzimidazole-linked indole compound acting as novel divalent IAP antagonist, specifically disclosing the compound shown in fomulas (I) or a pharmaceutically acceptable salt thereof.
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- Optimization of Blood-Brain Barrier Permeability with Potent and Selective Human Neuronal Nitric Oxide Synthase Inhibitors Having a 2-Aminopyridine Scaffold
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Effective delivery of therapeutic drugs into the human brain is one of the most challenging tasks in central nervous system drug development because of the blood-brain barrier (BBB). To overcome the BBB, both passive permeability and efflux transporter liability of a compound must be addressed. Herein, we report our optimization related to BBB penetration of neuronal nitric oxide synthase (nNOS) inhibitors toward the development of new drugs for neurodegenerative diseases. Various approaches, including enhancing lipophilicity and rigidity of new inhibitors and modulating the pKa of amino groups, have been employed. In addition to determining inhibitor potency and selectivity, crystal structures of most newly designed compounds complexed to various nitric oxide synthase isoforms have been determined. We have discovered a new analogue (21), which exhibits not only excellent potency (Ki 30 nM) in nNOS inhibition but also a significantly low P-glycoprotein and breast-cancer-resistant protein substrate liability as indicated by an efflux ratio of 0.8 in the Caco-2 bidirectional assay.
- Do, Ha T.,Li, Huiying,Chreifi, Georges,Poulos, Thomas L.,Silverman, Richard B.
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supporting information
p. 2690 - 2707
(2019/03/11)
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- HETEROCYCLIC DERIVATIVES AS ANTIBACTERIAL COMPOUNDS
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Compounds of Formula (I), or a stereoisomer or a pharmaceutically acceptable salt thereof, their preparation, pharmaceutical compositions comprising such compounds and their use in treating and/or preventing bacterial infections are disclosed.
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- Discovery of Pyrrolidine-Containing GPR40 Agonists: Stereochemistry Effects a Change in Binding Mode
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A novel series of pyrrolidine-containing GPR40 agonists is described as a potential treatment for type 2 diabetes. The initial pyrrolidine hit was modified by moving the position of the carboxylic acid, a key pharmacophore for GPR40. Addition of a 4-cis-CF3 to the pyrrolidine improves the human GPR40 binding Ki and agonist efficacy. After further optimization, the discovery of a minor enantiomeric impurity with agonist activity led to the finding that enantiomers (R,R)-68 and (S,S)-68 have differential effects on the radioligand used for the binding assay, with (R,R)-68 potentiating the radioligand and (S,S)-68 displacing the radioligand. Compound (R,R)-68 activates both Gq-coupled intracellular Ca2+ flux and Gs-coupled cAMP accumulation. This signaling bias results in a dual mechanism of action for compound (R,R)-68, demonstrating glucose-dependent insulin and GLP-1 secretion in vitro. In vivo, compound (R,R)-68 significantly lowers plasma glucose levels in mice during an oral glucose challenge, encouraging further development of the series.
- Jurica, Elizabeth A.,Wu, Ximao,Williams, Kristin N.,Hernandez, Andres S.,Nirschl, David S.,Rampulla, Richard A.,Mathur, Arvind,Zhou, Min,Cao, Gary,Xie, Chunshan,Jacob, Biji,Cai, Hong,Wang, Tao,Murphy, Brian J.,Liu, Heng,Xu, Carrie,Kunselman, Lori K.,Hicks, Michael B.,Sun, Qin,Schnur, Dora M.,Sitkoff, Doree F.,Dierks, Elizabeth A.,Apedo, Atsu,Moore, Douglas B.,Foster, Kimberly A.,Cvijic, Mary Ellen,Panemangalore, Reshma,Flynn, Neil A.,Maxwell, Brad D.,Hong, Yang,Tian, Yuan,Wilkes, Jason J.,Zinker, Bradley A.,Whaley, Jean M.,Barrish, Joel C.,Robl, Jeffrey A.,Ewing, William R.,Ellsworth, Bruce A.
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supporting information
p. 1417 - 1431
(2017/03/08)
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- As hepatitis c inhibitor spiro compound and its use in medicine
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The invention provides a spiro compound serving as a hepatitis c inhibitor and application thereof in a medicine. The compound is a compound as shown in a formula (I) or a stereisomer, a geometric isomer, a tautomer, nitric oxide, an aquo-complex, a solvate, a metabolite, pharmaceutically acceptable salt or prodrug of the compound as shown in the formula (I). The invention also provides a pharmaceutical composition containing the compound, application of the compound and the pharmaceutical composition in inhibition of HCV (Hepatitis C Virus) copy and HCV virus protein, as well as the application of the compound and the pharmaceutical composition in prevention, handling, treatment or relieving of HCV infection or hepatitis c disease for a patient. The formula I is as shown in the specification.
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- IMIDAZO[1,2-b]PYRIDAZINE DERIVATIVES AS KINASE INHIBITORS
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The present invention is intended to provide a compound or a pharmacologically acceptable salt thereof which is useful in the treatment of a tumor through its ROS1 kinase enzyme activity inhibitory effect and NTRK kinase enzyme inhibitory effect. The present invention provides a compound having an imidazo[1,2-b]pyridazine structure represented by the general formula (I) or a pharmacologically acceptable salt thereof, and a pharmaceutical composition comprising the compound. In the formula, R1, G, T, Y1, Y2, Y3, and Y4 are as defined herein.
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Paragraph 0254; 0255
(2016/03/13)
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- Bridged Ring compounds As Hepatitis C Virus (HCV) Inhibitors And Pharmaceutical Applications Thereof
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Provided herein is a compound having Formula (I), or a stereoisomer, a geometric isomer, a tautomer, an N-oxide, a hydrate, a solvate, a metabolite, a pharmaceutically acceptable salt or a prodrug thereof, which can be used for treating HCV infection or a HCV disorder. Also provided herein are pharmaceutical compositions comprising the compounds disclosed herein, which can be used for treating HCV infection or a HCV disorder.
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- 4-Fluoro and 4-hydroxy pyrrolidine-thioxotetrahydropyrimidinones: Organocatalysts for green asymmetric transformations in brine
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The synthesis of both trans- and cis-diastereomers of pyrrolidinine-thioxotetrahydropyrimidinone bearing either a fluorine or a hydroxyl group was accomplished. The new compounds were tested for their catalytic properties in a variety of asymmetric organic transformations and compared with the first generation catalyst. It was found that the new catalysts could efficiently catalyze the reactions in brine, without the use of organic solvent, and by employing an almost stoichiometric amount of reagents. Thus, the products were isolated by simple extractions, avoiding the use of chromatography in excellent yields, diastereoselectivities, and enantioselectivities.
- Kaplaneris, Nikolaos,Koutoulogenis, Giorgos,Raftopoulou, Marianna,Kokotos, Christoforos G.
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p. 5464 - 5473
(2015/06/16)
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- Synthesis and pharmacological evaluation of α4β2 nicotinic ligands with a 3-fluoropyrrolidine nucleus
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Abstract Nicotinic acetylcholine receptors (nAChRs) play an important role in many central nervous system disorders such as Alzheimer's and Parkinson's diseases, schizophrenia, and mood disorders. The α4β2 subtype has emerged as an important target for the early diagnosis and amelioration of Alzheimer's disease symptoms. Herein we report a new class of α4β2 receptor ligands characterized by a basic pyrrolidine nucleus, the basicity of which was properly decreased through the insertion of a fluorine atom at the 3-position, and a pyridine ring carrying at the 3-position substituents known to positively affect affinity and selectivity toward the α4β2 subtype. Derivatives 3-(((2S,4R)-4-fluoropyrrolidin-2-yl)methoxy)-5-(phenylethynyl)pyridine (11) and 3-((4-fluorophenyl)ethynyl)-5-(((2S,4R)-4-fluoropyrrolidin-2-yl)methoxy)pyridine (12) were found to be the most promising ligands identified in this study, showing good affinity and selectivity for the α4β2 subtype and physicochemical properties predictive of a relevant central nervous system penetration. Basicity tuned by F: By combining structural features of niodene and compound B, we developed new α4β2 receptor ligands characterized by the 3-fluoropyrrolidine nucleus. Derivatives (2S,4R)-11 and (2S,4R)-12 were highlighted as the most promising ligands identified in this study, showing good affinity and selectivity for the α4β2 subtype and physicochemical properties predictive of good central nervous system penetration.
- Tamborini, Lucia,Pinto, Andrea,Ettari, Roberta,Gotti, Cecilia,Fasoli, Francesca,Conti, Paola,De Micheli, Carlo
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p. 1071 - 1078
(2015/06/08)
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- IMIDAZO[1,2-b]PYRIDAZINE DERIVATIVES AS KINASE INHIBITORS
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The present invention is intended to provide a compound or a pharmacologically acceptable salt thereof which is useful in the treatment of a tumor through its ROS1 kinase enzyme activity inhibitory effect and NTRK kinase enzyme inhibitory effect. The present invention provides a compound having an imidazo[1,2-b]pyridazine structure represented by the general formula (I) or a pharmacologically acceptable salt thereof, and a pharmaceutical composition comprising the compound. In the formula, R1, G, T, Y1, Y2, Y3, and Y4 are as defined herein.
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Paragraph 0198-0199
(2015/02/25)
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- BRIDGED RING COMPOUNDS AS HEPATITIS C VIRUS (HCV) INHIBITORS AND PHARMACEUTICAL APPLICATIONS THEREOF
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Provided herein is a compound having Formula (I), or a stereoisomer, a geometric isomer, a tautomer, an N-oxide, a hydrate, a solvate, a metabolite, a pharmaceutically acceptable salt or a prodrug thereof, which can be used for treating HCV infection or a HCV disorder. Also provided herein are pharmaceutical compositions comprising the compounds disclosed herein, which can be used for treating HCV infection or a HCV disorder.
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- BRIDGED RING COMPOUNDS AS HEPATITIS C VIRUS INHIBITORS, PHARMACEUTICAL COMPOSITIONS AND USES THEREOF
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Provided herein is a compound of formula (I) or a stereoisomer, a geometric isomer, a tautomer, an N-oxide, a hydrate, a solvate, a metabolite, a pharmaceutically acceptable salt or a prodrug thereof, which can be used for treating HCV infection or a HCV disorder. Also provided herein are a pharmaceutical composition comprising the compound and the use of the compound and the pharmaceutical composition thereof, which can also be used for treating HCV infection or a HCV disorder.
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- Influence of 4- or 5-substituents on the pyrrolidine ring of 5-[1-(2-methoxymethylpyrrolidinyl)sulfonyl]isatin derivatives on their inhibitory activities towards caspases-3 and -7 Dedicated to Professor Dr. Ernst-Ulrich Würthwein on the occasion of his 65th birthday
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A series of new 4- or 5-substituted pyrrolidine derivatives of 5-[1-(2-methoxymethylpyrrolidinyl)sulfonyl]isatin bearing additional n-butyl or 4-fluorobutyl groups at the isatin nitrogen were prepared and their inhibitory activities have been tested against caspases-3 and -7, which are known to participate in the execution of the programmed cell death, called apoptosis. Several analogues fluorinated at the 4-position of the pyrrolidine ring were also synthesized since such inhibitors might be developed as 18F-radiotracers for molecular imaging of activated caspases in vivo by PET. Enantiomerically pure diastereomeric 4-fluoropyrrolidinyl derivatives inhibited the enzymes in the nanomolar scale, i.e.100-1000 times more efficient than the corresponding 4-methoxy analogues. The 4,4-difluorinated compound showed the best result with IC50 = 362 nM and 178 nM for the aforementioned caspases. In contrast, the 4-methoxy and 4-trifluoromethyl analogues exhibited less inhibition potencies for the enzymes in the μM scale, whereas all 4-OPEG4 (PEG4 = tetraethyleneglycol) and 5-methoxymethyl derivatives were inactive.
- Limpachayaporn, Panupun,Riemann, Burkhard,Kopka, Klaus,Schober, Otmar,Sch?fers, Michael,Haufe, Günter
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p. 562 - 578
(2013/07/11)
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- PYRROLIDINE GPR40 MODULATORS
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The present invention provides compounds of Formula (I): or a stereoisomer, or a pharmaceutically acceptable salt thereof, wherein all of the variables are as defined herein. These compounds are GPR40 G protein-coupled receptor modulators which may be used as medicaments.
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Page/Page column 35
(2011/04/24)
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- Novel series of pyrrolotriazine analogs as highly potent pan-Aurora kinase inhibitors
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The synthesis and SAR for a novel series of pyrrolotriazines as pan-Aurora kinase inhibitors are described. Optimization of the cyclopropane carboxamide terminus of lead compound 1 resulted in analogs with high cellular activity and improved rat PK profiles. Notably, compound 17l demonstrated tumor growth inhibition in a mouse xenograft model.
- Abraham, Sunny,Hadd, Michael J.,Tran, Lan,Vickers, Troy,Sindac, Janice,Milanov, Zdravko V.,Holladay, Mark W.,Bhagwat, Shripad S.,Hua, Helen,Ford Pulido, Julia M.,Cramer, Merryl D.,Gitnick, Dana,James, Joyce,Dao, Alan,Belli, Barbara,Armstrong, Robert C.,Treiber, Daniel K.,Liu, Gang
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supporting information; scheme or table
p. 5296 - 5300
(2011/10/08)
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- Substituted Disulfonamide Compounds
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Substituted disulfonamide compounds corresponding to formula I: In which R1, R2, R3, R4a, R4b, R5a, R5b, R8, R9a, R9b, R10, R11, a, b, s, t and A have defined meanings, pharmaceutical compositions containing one or more such compounds, processes for preparing such compounds, and a method of using such compounds for the treatment or inhibition of pain and/or other conditions mediated by the bradykinin receptor 1 (BR1).
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Page/Page column 29
(2010/06/22)
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- NOVEL COMPOUNDS AS CANNABINOID RECEPTOR LIGANDS
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The present application relates to cannabinoid receptor ligands of formula (I) wherein X1, A1, Rx, R2, R3, R4, and z are as defined in the specification. The present application also relates to compositions comprising such compounds, and methods for treating conditions and disorders using such compounds and compositions.
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Page/Page column 33
(2010/04/23)
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- Synthesis, SAR, and X-ray structure of novel potent DPPIV inhibitors: Oxadiazolyl ketones
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Synthesis of a novel series of DPPIV inhibitors with 1,2,4- and 1,3,4-oxadiazolyl ketone derivatives and its structure-activity relationships are discussed. Compound 18h showed good inhibitory activity against DPPIV and favorable pharmacokinetic properties. In vivo pharmacodynamic efficacy and co-crystal structure of compound 18h with DPPIV is also described.
- Koo, Ki Dong,Kim, Min Jung,Kim, Sungsub,Kim, Kyoung-Hee,Hong, Sang Yong,Hur, Gwong-Cheung,Yim, Hyeon Joo,Kim, Geun Tae,Han, Hee Oon,Kwon, O Hwan,Kwon, Tae Sik,Koh, Jong Sung,Lee, Chang-Seok
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p. 4167 - 4172
(2008/02/09)
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- An efficient solid-phase synthesis of biologically important DNA-interactive pyrrolo[2,1-c][1,4]benzodiazepine dimers (DSB-120) and their C2-fluorinated analogues
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A facile method for the solid-phase synthesis of pyrrolo[2,1-c][1,4]benzodiazepine dimers has been developed. p-Nitrophenyl carbonate Wang resin attached to 2-amino-5-methoxy-methyl benzoate has been utilized as the resin-bound starting material and these reactions are monitored by FT-IR spectroscopy of resin beads.
- Kamal, Ahmed,Shankaraiah,Devaiah,Reddy, K. Laxma
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p. 6553 - 6556
(2007/10/03)
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- 4-(Pyrrolidinyl)methoxybenzoic acid derivatives as a potent, orally active VLA-4 antagonist
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A novel series of benzoic acid derivatives as VLA-4 antagonists were synthesized. Optimization, focusing on activity and lipophilicity needed for cell permeability, resulted in the identification of 15b and 15e with good activity (IC50=1.6 nM each) and moderate lipophilicity (Log D=2.0, 1.8). Furthermore, 15e demonstrated efficacy in murine asthma model by an oral dose of 30 mg/kg.
- Chiba, Jun,Iimura, Shin,Yoneda, Yoshiyuki,Sugimoto, Yuichi,Horiuchi, Takao,Muro, Fumito,Ochiai, Yuichi,Ogasawara, Tomomi,Tsubokawa, Masao,Iigou, Yutaka,Takayama, Gensuke,Taira, Tomoe,Takata, Yoshimi,Yokoyama, Mika,Takashi, Tohru,Nakayama, Atsushi,Machinaga, Nobuo
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p. 1515 - 1529
(2007/10/03)
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- The synthesis and biological activity of C2-fluorinated pyrrolo[2,1-c][1,4]benzodiazepines
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The novel C2-fluorinated pyrrolobenzodiazepines (1, 2 and 3) have been prepared from commercially available trans-hydroxyproline in good overall yield and were screened for in vitro cytotoxicity against a number of cancer cell lines. The 2R-fluoro isomer 2 exhibits an activity of 76 nM against the CH1 cell line.
- O'Neil, Ian A.,Thompson, Stephen,Kalindjian, S. Barret,Jenkins, Terence C.
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p. 7809 - 7812
(2007/10/03)
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