- TRANSGLUTAMINASE 2 (TG2) INHIBITORS
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Described herein are compounds and pharmaceutical compositions containing such compounds which inhibit transglutaminase 2 (TG2). Also described herein are methods for using such TG2 inhibitors, alone or in combination with other compounds, for treating diseases or conditions that would benefit from TG2 inhibition.
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Paragraph 001007
(2020/03/02)
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- N8-Glycosylated 8-Azapurine and Methylated Purine Nucleobases: Synthesis and Study of Base Pairing Properties
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In this report, we present the synthesis of N8-glycosylated 8-aza-2-methylhypoxanthine and 8-aza-6-thiohypoxanthine 2′-deoxynucleosides as well as methylated 2′-deoxynebularine derivatives. In vitro base pairing properties between each modified and canonical nucleobase were studied. As demonstrated by Tm, incorporation of the modified bases in DNA resulted, with few exceptions, in low stability of duplexes. Modified bases studied in this report are preferentially recognized by T (for N8-glycosylated 8-aza-2-methylhypoxanthine and methylated purines) and G (N8-glycosylated 8-aza-2-methylhypoxanthine). The base pair formed between N8-glycosylated 8-aza-6-thiohypoxanthine and N9-glycosylated 2-methyl-6-thiohypoxanthine (X2:X6) showed, to some extent, an orthogonal interaction. Based on Tm studies, the only potential self-pairing system is formed by the N8-glycosylated 8-aza-6-thiohypoxanthine nucleoside (X2) but only in the absence of canonical G and T. This study indicated that the canonical thymine base is the preferential base partner of methylated purine bases.
- Leonczak, Piotr,Srivastava, Puneet,Bande, Omprakash,Schepers, Guy,Lescrinier, Eveline,Herdewijn, Piet
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p. 13394 - 13409
(2019/11/03)
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- COMPOSITIONS AND METHODS USING THE SAME FOR TREATMENT OF NEURODEGENERATIVE AND MITOCHONDRIAL DISEASE
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The present disclosure is directed, in part, to compounds, or pharmaceutically acceptable salts thereof, for the treatment and/or prevention of neurodegenerative disease, mitchonodrial disease, fibrosis, and/or cardiomyopathy.
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Paragraph 0271
(2019/01/10)
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- PYRIMIDINE COMPOUNDS AND PYRIMIDO INDOLE COMPOUNDS AND METHODS OF USE
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The present invention discloses substituted pyrimidine and pyrimido indole compounds and optionally pharmaceutically acceptable salts, hydrates or solvates thereof. A method of treating a patient having cancer or a disease comprising administering to a patient an effective amount of the compound or pharmaceutically acceptable salt, hydrate, or solvate thereof.
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Page/Page column 64; 65
(2016/03/19)
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- TANK-BINDING KINASE INHIBITOR COMPOUNDS
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Compounds having the following formula (I) and methods of their use and preparation are disclosed:
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Page/Page column 167
(2015/12/24)
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- Selective cannabinoid receptor type 2 (CB2) agonists: Optimization of a series of purines leading to the identification of a clinical candidate for the treatment of osteoarthritic pain
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A focused screening strategy identified thienopyrimidine 12 as a cannabinoid receptor type 2 agonist (hCB2) with moderate selectivity over the hCB1 receptor. This initial hit suffered from poor in vitro metabolic stability and high in vivo clearance. Structure-activity relationships describe the optimization and modification to a new more polar series of purine CB2 agonists. Examples from this novel scaffold were found to be highly potent and fully efficacious agonists of the human CB2 receptor with excellent selectivity against CB1, often having no CB1 agonist activity at the highest concentration measured (>100 μM). Compound 26 is a centrally penetrant molecule which possesses good biopharmaceutical properties, is highly water-soluble, and demonstrates robust oral activity in rodent models of joint pain. In addition, the peripherally restricted molecule 22 also demonstrated significant efficacy in the same analgesic model of rodent inflammatory pain.
- Hollinshead, Sean P.,Tidwell, Michael W.,Palmer, John,Guidetti, Rossella,Sanderson, Adam,Johnson, Michael P.,Chambers, Mark G.,Oskins, Jennifer,Stratford, Robert,Astles, Peter C.
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p. 5722 - 5733
(2013/08/23)
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- Structure-based design of a novel series of potent, selective inhibitors of the class i phosphatidylinositol 3-kinases
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A highly selective series of inhibitors of the class I phosphatidylinositol 3-kinases (PI3Ks) has been designed and synthesized. Starting from the dual PI3K/mTOR inhibitor 5, a structure-based approach was used to improve potency and selectivity, resulting in the identification of 54 as a potent inhibitor of the class I PI3Ks with excellent selectivity over mTOR, related phosphatidylinositol kinases, and a broad panel of protein kinases. Compound 54 demonstrated a robust PD-PK relationship inhibiting the PI3K/Akt pathway in vivo in a mouse model, and it potently inhibited tumor growth in a U-87 MG xenograft model with an activated PI3K/Akt pathway.
- Smith, Adrian L.,D'Angelo, Noel D.,Bo, Yunxin Y.,Booker, Shon K.,Cee, Victor J.,Herberich, Brad,Hong, Fang-Tsao,Jackson, Claire L. M.,Lanman, Brian A.,Liu, Longbin,Nishimura, Nobuko,Pettus, Liping H.,Reed, Anthony B.,Tadesse, Seifu,Tamayo, Nuria A.,Wurz, Ryan P.,Yang, Kevin,Andrews, Kristin L.,Whittington, Douglas A.,McCarter, John D.,Miguel, Tisha San,Zalameda, Leeanne,Jiang, Jian,Subramanian, Raju,Mullady, Erin L.,Caenepeel, Sean,Freeman, Daniel J.,Wang, Ling,Zhang, Nancy,Wu, Tian,Hughes, Paul E.,Norman, Mark H.
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experimental part
p. 5188 - 5219
(2012/08/28)
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- Discovery and optimization of novel purines as potent and selective CB2 agonists
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A focused screening strategy identified thienopyrimidine 1 as a hCB2 cannabinoid receptor agonist with moderate selectivity over the hCB1 receptor. This initial hit suffered from poor in vitro metabolic stability and high in vivo clearance. Structure-activity relationships describe the optimization and modification to a less lipophilic purine core. Examples from this novel series were found to be highly potent and fully efficacious agonists of the human CB2 receptor with excellent selectivity against CB1. Compound 10 possesses good biopharmaceutical properties, is highly water soluble and demonstrates robust oral activity in rodent models of joint pain.
- Hollinshead, Sean P.,Astles, Peter C.,Chambers, Mark G.,Johnson, Michael P.,Palmer, John,Tidwell, Michael W.
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scheme or table
p. 4962 - 4966
(2012/09/07)
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- PTERIDINES AND THEIR USE AS AGROCHEMICALS
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The present disclosure relates to 1- or 2-(4-(aryloxy)-phenyl)ethylamino-, oxy- or sulfanyl)pteridines and 1- or 2-(4-(heteroaryloxy)-phenyl)ethylamino-, oxy- or sulfanyl)pteridines and their use as agrochemicals and animal health products.
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Page/Page column 21
(2011/04/14)
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- PTERIDINES AND THEIR USE AS AGROCHEMICALS
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The present disclosure relates to 1- or 2-(4-(aryloxy)-phenyl)ethylamino-, oxy- or sulfanyl)pteridines and 1- or 2-(4-(heteroaryloxy)-phenyl)ethylamino-, oxy- or sulfanyl)pteridines and their use as agrochemicals and animal health products.
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Page/Page column 49
(2011/04/14)
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- PURINE COMPOUNDS
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A compound of the formula: and pharmaceutical compositions for the treatment or prevention of pain.
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Page/Page column 6
(2011/10/13)
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- HETEROARYL COMPOUNDS AS PIKK INHIBITORS
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The present invention provides compounds that are PIKK inhibitors, more specifically, mTOR and/or PI3Kα kinase inhibitors and are therefore useful for the treatment of diseases treatable by inhibition of kinases, specifically PI3 kinases, more specifically, mTOR and/or PI3Kα, such as cancer. Also provided are pharmaceutical compositions containing such compounds and processes for preparing such compounds.
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Page/Page column 75
(2010/12/17)
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- NOVEL COMPOUNDS
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The present invention relates to a class of substituted purine compounds of formula (I), uses thereof, processes for the preparation thereof and compositions containing said compounds. These compounds have utility in a variety of therapeutic areas including sexual dysfunction.(I).
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Page/Page column 62
(2009/12/27)
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- Imidazolopyrimidine modulators of TRPV1
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Certain TRPV1-modulating imidazolopyrimidine compounds are described. The compounds may be used in pharmaceutical compositions and methods for treating disease states, disorders, and conditions mediated by TRPV1 activity, such as pain, arthritis, itch, cough, asthma, or inflammatory bowel disease.
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Page/Page column 10
(2009/07/03)
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