- Projected Dose Optimization of Amino- And Hydroxypyrrolidine Purine PI3KδImmunomodulators
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The approvals of idelalisib and duvelisib have validated PI3Kδinhibitors for the treatment for hematological malignancies driven by the PI3K/AKT pathway. Our program led to the identification of structurally distinct heterocycloalkyl purine inhibitors wit
- Methot, Joey L.,Zhou, Hua,McGowan, Meredeth A.,Anthony, Neville John,Christopher, Matthew,Garcia, Yudith,Achab, Abdelghani,Lipford, Kathryn,Trotter, Benjamin Wesley,Altman, Michael D.,Fradera, Xavier,Lesburg, Charles A.,Li, Chaomin,Alves, Stephen,Chappell, Craig P.,Jain, Renu,Mangado, Ruban,Pinheiro, Elaine,Williams, Sybill M. G.,Goldenblatt, Peter,Hill, Armetta,Shaffer, Lynsey,Chen, Dapeng,Tong, Vincent,McLeod, Robbie L.,Lee, Hyun-Hee,Yu, Hongshi,Shah, Sanjiv,Katz, Jason D.
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Read Online
- Structure Overhaul Affords a Potent Purine PI3KδInhibitor with Improved Tolerability
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PI3Kδcatalytic activity is required for immune cell activation, and has been implicated in inflammatory diseases as well as hematological malignancies in which the AKT pathway is overactive. A purine PI3Kδinhibitor bearing a benzimidazolone-piperidine motif was found to be poorly tolerated in dog, which was attributed to diffuse vascular injury. Several strategies were implemented to mitigate this finding, including reconstruction of the benzimidazolone-piperidine selectivity motif. Structure-based design led to the identification of O- and N-linked heterocycloalkyls, with pyrrolidines being particularly ligand efficient and kinome selective, and having an improved safety pharmacology profile. A representative was advanced into a dog tolerability study where it was found to be well tolerated, with no histopathological evidence of vascular injury.
- Methot, Joey L.,Zhou, Hua,Kattar, Sam D.,Mcgowan, Meredeth A.,Wilson, Kevin,Garcia, Yudith,Deng, Yongi,Altman, Michael,Fradera, Xavier,Lesburg, Charles,Fischmann, Thierry,Li, Chaomin,Alves, Steve,Shah, Sanjiv,Fernandez, Rafael,Goldenblatt, Peter,Hill, Armetta,Shaffer, Lynsey,Chen, Dapeng,Tong, Vince,Mcleod, Robbie L.,Yu, Hongshi,Bass, Alan,Kemper, Ray,Gatto, Nicholas T.,Lafranco-Scheuch, Lisa,Trotter, Benjamin Wesley,Guzi, Timothy,Katz, Jason D.
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p. 4370 - 4382
(2019/05/08)
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- Use of Inhibitors of the Activity or Function of PI3K
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The invention relates to new uses of PI3K inhibitors, wherein said inhibitors have an inhibitory action on the PI3K isoform delta for the treatment of immunopathology in a subject suffering from a disease or disorder selected from malaria, leishmaniasis, trypanosomiasis, toxoplasmosis and/or neurocysticercosis, via functional inhibition of TLR9 of the infected subject.
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Paragraph 0808
(2016/01/09)
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- Dihydro-Benzo-Oxazine and Dihydro-Pyrido-Oxazine Derivatives
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The invention relates to dihydro-benzo-oxazine and dihydro-pyrido-oxazine compounds of the formula (I) and/or pharmaceutically acceptable salts and/or solvates thereof, wherein Y, V, W, U, Q, R1, R5, R7 and R30 are as defined in the description. Such compounds are suitable for the treatment of a disorder or disease which is mediated by the activity of the PI3K enzymes.
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Paragraph 0826; 0827; 0828; 0829
(2013/07/05)
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- SOLID FORMS AND SALTS OF TETRAHYDRO-PYRIDO-PYRIMIDINE DERIVATIVES
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The invention relates to crystalline anhydrous forms, crystalline solvate forms and/or salt forms including crystalline salt forms of {(S)-3-[6-(6-methoxy-5-methyl-pyridin-3-yl)-5,6,7,8- tetrahydro-pyrido[4,3-d]pyrimidin-4-yloxy]-pyrrolidin-1-yl}-(tetrahydro-pyran-4-yl)-methanone or salt forms including crystalline salt forms of 1-{(S)-3-[6-(6-methoxy-5-trifluoromethyl- pyridin-3-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-ylamino]-pyrrolidin-1-yl}-propan-1-on; pharmaceutical compositions and combinations including these forms as well as to methods of using these forms, including their pharmaceutical compositions and combinations for the treatment of diseases.
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Page/Page column 38
(2013/03/26)
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- Use of inhibitors of the activity or function of PI3K
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The invention relates to new uses of PI3K inhibitors, wherein said inhibitors have an inhibitory action on the PI3K isoform delta for the treatment of immunopathology in a subject suffering from a disease or disorder selected from malaria, leishmaniasis, trypanosomiasis, toxoplasmosis and/or neurocysticercosis, via functional inhibition of TLR9 of the infected subject.
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Page/Page column 75
(2013/07/05)
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- TETRAHYDRO-PYRIDO-PYRIMIDINE DERIVATIVES
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The invention relates to substituted tetrahydro-pyrido-pyrimidine derivatives of the formula (I), wherein Y, R1, R2 and m are as defined in the description. Such compounds are suitable for the treatment of a disorder or disease which
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Page/Page column 68
(2012/02/01)
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