- Lead Optimization of 3,5-Disubstituted-7-Azaindoles for the Treatment of Human African Trypanosomiasis
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Neglected tropical diseases such as human African trypanosomiasis (HAT) are prevalent primarily in tropical climates and among populations living in poverty. Historically, the lack of economic incentive to develop new treatments for these diseases has meant that existing therapeutics have serious shortcomings in terms of safety, efficacy, and administration, and better therapeutics are needed. We now report a series of 3,5-disubstituted-7-azaindoles identified as growth inhibitors of Trypanosoma brucei, the parasite that causes HAT, through a high-throughput screen. We describe the hit-to-lead optimization of this series and the development and preclinical investigation of 29d, a potent antitrypanosomal compound with promising pharmacokinetic (PK) parameters. This compound was ultimately not progressed beyond in vivo PK studies due to its inability to penetrate the blood-brain barrier (BBB), critical for stage 2 HAT treatments.
- Klug, Dana M.,Mavrogiannaki, Eftychia M.,Forbes, Katherine C.,Silva, Lisseth,Diaz-Gonzalez, Rosario,Pérez-Moreno, Guiomar,Ceballos-Pérez, Gloria,Garcia-Hernández, Raquel,Bosch-Navarrete, Cristina,Cordón-Obras, Carlos,Gómez-Li?án, Claudia,Saura, Andreu,Momper, Jeremiah D.,Martinez-Martinez, Maria Santos,Manzano, Pilar,Syed, Ali,El-Sakkary, Nelly,Caffrey, Conor R.,Gamarro, Francisco,Ruiz-Perez, Luis Miguel,Gonzalez Pacanowska, Dolores,Ferrins, Lori,Navarro, Miguel,Pollastri, Michael P.
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p. 9404 - 9430
(2021/07/25)
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- 5-(1H-Pyrazol-4-yl)-1H-Pyrrolo[2,3-b]Pyridine Derivatives as Kinase Inhibitors
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The present application relates to novel 5-(1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridine derivatives of formula (I), as protein kinase inhibitors. The invention particularly relates to compounds of formula (I), preparation of compounds and pharmaceutical compositions thereof. The invention further relates to prodrugs, derivatives, polymorphs, pharmaceutically acceptable salts and compositions comprising the said novel 5-(1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridine compounds and their derivatives and their use in the treatment of various disorders.
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- 5-(1H-PYRAZOL-4-YL)-1H-PYRROLO[2,3-b]PYRIDINE DERIVATIVES AS KINASE INHIBITORS
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The present application relates to novel 5-(1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridine derivatives of formula (I), as protein kinase inhibitors. The invention particularly relates to compounds of formula (I), preparation of compounds and pharmaceutical compositions thereof. The invention further relates to prodrugs, derivatives, polymorphs, pharmaceutically acceptable salts and compositions comprising the said novel 5-(1H-pyrazol-4-yl)-1H- pyrrolo[2,3-b]pyridine compounds and their derivatives and their use in the treatment of various disorders.
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Page/Page column 34; 35
(2014/03/21)
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- Discovery of 7-azaindole based anaplastic lymphoma kinase (ALK) inhibitors: Wild type and mutant (L1196M) active compounds with unique binding mode
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We have identified a novel 7-azaindole series of anaplastic lymphoma kinase (ALK) inhibitors. Compounds 7b, 7m and 7n demonstrate excellent potencies in biochemical and cellular assays. X-ray crystal structure of one of the compounds (7k) revealed a unique binding mode with the benzyl group occupying the back pocket, explaining its potency towards ALK and selectivity over tested kinases particularly Aurora-A. This binding mode is in contrast to that of known ALK inhibitors such as Crizotinib and NVP-TAE684 which occupy the ribose binding pocket, close to DFG motif.
- Gummadi, Venkateshwar Rao,Rajagopalan, Sujatha,Looi, Chung-Yeng,Paydar, Mohammadjavad,Renukappa, Girish Aggunda,Ainan, Bharathi Raja,Krishnamurthy, Narasimha Rao,Panigrahi, Sunil Kumar,Mahasweta, Kumari,Raghuramachandran, Sangeetha,Rajappa, Manoj,Ramanathan, Anuradha,Lakshminarasimhan, Anirudha,Ramachandra, Murali,Wong, Pooi-Fong,Mustafa, Mohammad Rais,Nanduri, Srinivas,Hosahalli, Subramanya
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p. 4911 - 4918
(2013/09/02)
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- 3-HETARYL-SUBSTITUTED PYRROLO[2,3 B]PYRIDINE DERIVATIVES AS PDK1 INHIBITORS
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Compounds of the formula I in which Q, R1, R2, R3 and R4 have the meanings indicated in Claim 1, are PDK1 inhibitors and can be employed for the treatment of tumours.
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- 7-AZAINDOLE DERIVATIVES
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Compounds of the formula (I) in which R, R1, R2 and R3 have the meanings indicated in Claim 1, are inhibitors of PDK1 and cell proliferation/cell vitality and can be employed for the treatment of tumours.
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Paragraph 0230; 0231
(2013/12/03)
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- 3-(1,2,3-Triazol-4-yl) pyrrolo [2,3-b] pyridine derivatives
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Compounds of the formula (I), in which R1, R2 and R3 have the meanings indicated in claim (1), are inhibitors of PDK1 and cell proliferation/cell vitality and can be employed for the treatment of tumours.
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Page/Page column 14
(2012/03/12)
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