- Evaluation of WO2014075392 and WO2014075393, Merck's first PI3Kδ inhibitor filings
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Introduction: There is considerable interest in the development of selective PI3Kδ inhibitors for the treatment of inflammatory diseases and haematological cancers. Merck has no previous filings in this field but licensed Exelixis' programme, including its lead compound XL-499, in December 2011.Areas covered: Both applications claim novel 9-alkyl-6,8-disubstituted purine derivatives as selective δ inhibitors for the treatment of asthma, obstructive airways disease, arthritis and cancer. The two applications differ in the range of exemplified substituents, the first focusing on 8-heteroaryl substituted purines, the second on 8-aminopurine derivatives. Many of the exemplified compounds have IC50 values a number having sub-nanomolar potency.Expert Opinion: The compounds appear to be XL-499 derivatives, some of which are more potent than XL-499. The compounds claimed by Merck are some of the most potent PI3Kδ inhibitors yet described but it is unclear whether a development compound has been identified.
- Norman, Peter
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Read Online
- 3,4-dichloroisothiazole heterocyclic purine derivatives as well as preparation method and application thereof
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The invention provides a 3,4-dichloroisothiazole bipurine derivative as well as a preparation method and application thereof, and particularly relates to the 3,4-dichloroisothiazole bipurine derivative of which the chemical structural general formula is s
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Paragraph 0072-0074; 0109
(2021/06/13)
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- Design, Synthesis, and Evaluation of Novel Isothiazole-Purines as a Pyruvate Kinase-Based Fungicidal Lead Compound
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Target identification is one of the most important bases for novel pesticide development; pyruvate kinase (PK) was discovered as a potent fungicide target in our previous studies. To continue the PK-based fungicide development, novel isothiazole-purine derivatives were rationally designed and synthesized. Bioassay results showed that compound 5ai displayed excellent in vitro activity against Rhizoctonia solani with an EC50 of 1.5 μg/mL, which was superior to those of positive controls diflumetorim with its EC50 of 19.8 μg/mL and PK-based lead YZK-C22 with its EC50 of 4.2 μg/mL. Compounds 3b (5.2 μg/mL) and 3c (4.5 μg/mL) displayed better activities against Gibberella zeae with their EC50s falling between 4.0 and 5.5 μg/mL, while YZK-C22 showed an EC50 of 6.4 μg/mL. In addition, 5ah exhibited promising in vivo activity against Erysiphe graminis and Puccinia sorghi Schw. with 100% efficacy at 10 μg/mL and 90% efficacy at 2 μg/mL against P. sorghi Schw. Compound 5ai showed good PK inhibitory activity with an IC50 of 38.8 μmol/L, and it was well docked into the active site of the target enzyme PK, which was slightly more active than YZK-C22 with its IC50 of 42.4 μmol/L. Our studies discovered that isothiazole-purines were PK-based fungicidal leads deserving of further study.
- Fan, Zhijin,Gao, Wei,Hao, Zesheng,Li, Kun,Li, Zhixinyi,Liu, Xiaoyu,Lv, You,Tang, Liangfu,Wang, Weibo,Zhao, Bin
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p. 9461 - 9471
(2021/09/03)
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- New potent and selective A1 adenosine receptor antagonists as potential tools for the treatment of gastrointestinal diseases
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The synthesis of 9-alkyl substituted adenine derivatives presenting aromatic groups and cycloalkyl rings in 8- and N6-position, respectively, is reported. The compounds were tested with radioligand binding studies showing, in some cases, a low
- Lambertucci, Catia,Marucci, Gabriella,Dal Ben, Diego,Buccioni, Michela,Spinaci, Andrea,Kachler, Sonja,Klotz, Karl-Norbert,Volpini, Rosaria
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p. 199 - 213
(2018/04/05)
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- PURINE INHIBITORS OF HUMAN PHOSPHATIDYLINOSITOL 3-KINASE DELTA
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The instant invention provides compounds of formula (I) which are PI3K-delta inhibitors, and as such are useful for the treatment of PI3K-delta-mediated diseases such as inflamation, asthma, COPD and cancer.
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Page/Page column 59
(2017/11/01)
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- PURINE INHIBITORS OF HUMAN PHOSPHATIDYLINOSITOL 3-KINASE DELTA
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Provided are compounds of formula (I) or a pharmaceutically acceptable salts or stereoisomer thereof, which are PI3K-delta inhibitors, and are useful for the treatment of PI3K-delts-mediated diseases such as inflammation, asthma, COPD and cancer.
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Page/Page column 51
(2017/01/26)
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- PURINE INHIBITORS OF HUMAN PHOSPHATIDYLINOSITOL 3-KINASE DELTA
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Provided are compounds of formula I which are PI3K-delta inhibitors, and as such are useful for the treatment of PI3K-delta-mediated diseases such as inflammation, asthma, COPD and cancer.
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Page/Page column 39
(2016/01/01)
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- PURINE INHIBITORS OF HUMAN PHOSPHATIDYLINOSITOL 3-KINASE DELTA
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The instant invention provides compounds of formula I which are PI3K-delta inhibitors, and as such are useful for the treatment of PI3K-delta-mediated diseases such as inflamation, asthma, COPD and cancer.
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Page/Page column 66; 68
(2014/06/11)
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- PURINE INHIBITORS OF HUMAN PHOSPHATIDYLINOSITOL 3-KINASE DELTA
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The instant invention provides compounds of formula I which are PI3K-delta inhibitors, and as such are useful for the treatment of PI3K-delta-mediated diseases such as inflamation, asthma, COPD and cancer.
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Page/Page column 62
(2014/06/11)
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- 8-Bromo-9-alkyl adenine derivatives as tools for developing new adenosine A2A and A2B receptors ligands
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Importance of making available selective adenosine receptor antagonists is boosted by recent findings of adenosine involvement in many CNS dysfunctions. In the present work a series of 8-bromo-9-alkyl adenines are prepared and fully characterized in radio
- Lambertucci, Catia,Antonini, Ippolito,Buccioni, Michela,Dal Ben, Diego,Kachare, Dhuldeo D.,Volpini, Rosaria,Klotz, Karl-Norbert,Cristalli, Gloria
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experimental part
p. 2812 - 2822
(2009/09/08)
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- An efficient one-pot synthesis of 6-alkoxy-8,9-dialkylpurines via reaction of 5-amino-4-chloro-6-alkylaminopyrimidines with N,N-dimethylalkaneamides and alkoxide ions
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The synthesis of a number of new 6-alkoxy-8,9-(disubstituted)purines has been accomplished by the cyclization of the corresponding intermediate 5-amino-4-chloro-6-(alkylamino)pyrimidines promoted by alkoxides and various N,N-dimethyl amides, where the latter act as solvent-reagents. By this three-component condensation reaction we are able to introduce an alkyl group in the 8 position of the purine ring with the concomitant nucleophilic replacement of the 6-chloro group with an alkoxy moiety.
- Baraldi, Pier Giovanni,Broceta, Asier Unciti,Infantas, Maria Josè Pineda De Las,Mochun, Juan Josè Dìaz,Espinosa, Antonio,Romagnoli, Romeo
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p. 7607 - 7611
(2007/10/03)
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- Efficient synthesis of purine analogues: An FeCl3-SiO2-promoted cyclization reaction of 4,5-diaminopyrimidines with aldehydes leading to 6,8,9-trisubstituted purines
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6,8,9-Trisubstituted purine analogues were efficiently synthesized via cyclization of 6-chloro-4,5-diaminopyrimidines and various aldehydes promoted by FeCl3-SiO2. Fe(III) chloride on silica gel has a dual role of a dehydration agent
- Dang,Brown,Erion
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p. 6559 - 6562
(2007/10/03)
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