- FUSED PYRAZOLE AND IMIDAZOLE BASED COMPOUNDS AND USE THEREOF AS GLI1 INHIBITORS
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The present invention is directed to a composition and a method for use thereof, such as for the treatment and prevention of a neurological disorder or cancer in a subject.
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Paragraph 00197; 00201
(2021/11/20)
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- HETEROARYL SUBSTITUTED BENZOIC ACIDS AS RORGAMMAT INHIBITORS AND USES THEREOF
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The present invention relates to compounds according to Formula I and pharmaceutically acceptable salts thereof. Such compounds can be used in the treatment of RORgammaT-mediated diseases or conditions.
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Paragraph 00158
(2017/05/17)
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- Discovery of 2-[1-(4,4-Difluorocyclohexyl)piperidin-4-yl]-6-fluoro-3-oxo-2,3-dihydro-1H-isoindole-4-carboxamide (NMS-P118): A Potent, Orally Available, and Highly Selective PARP-1 Inhibitor for Cancer Therapy
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The nuclear protein poly(ADP-ribose) polymerase-1 (PARP-1) has a well-established role in the signaling and repair of DNA and is a prominent target in oncology, as testified by the number of candidates in clinical testing that unselectively target both PARP-1 and its closest isoform PARP-2. The goal of our program was to find a PARP-1 selective inhibitor that would potentially mitigate toxicities arising from cross-inhibition of PARP-2. Thus, an HTS campaign on the proprietary Nerviano Medical Sciences (NMS) chemical collection, followed by SAR optimization, allowed us to discover 2-[1-(4,4-difluorocyclohexyl)piperidin-4-yl]-6-fluoro-3-oxo-2,3-dihydro-1H-isoindole-4-carboxamide (NMS-P118, 20by). NMS-P118 proved to be a potent, orally available, and highly selective PARP-1 inhibitor endowed with excellent ADME and pharmacokinetic profiles and high efficacy in vivo both as a single agent and in combination with Temozolomide in MDA-MB-436 and Capan-1 xenograft models, respectively. Cocrystal structures of 20by with both PARP-1 and PARP-2 catalytic domain proteins allowed rationalization of the observed selectivity.
- Papeo, Gianluca,Posteri, Helena,Borghi, Daniela,Busel, Alina A.,Caprera, Francesco,Casale, Elena,Ciomei, Marina,Cirla, Alessandra,Corti, Emiliana,D'Anello, Matteo,Fasolini, Marina,Forte, Barbara,Galvani, Arturo,Isacchi, Antonella,Khvat, Alexander,Krasavin, Mikhail Y.,Lupi, Rosita,Orsini, Paolo,Perego, Rita,Pesenti, Enrico,Pezzetta, Daniele,Rainoldi, Sonia,Riccardi-Sirtori, Federico,Scolaro, Alessandra,Sola, Francesco,Zuccotto, Fabio,Felder, Eduard R.,Donati, Daniele,Montagnoli, Alessia
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p. 6875 - 6898
(2015/09/22)
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- 3-OXO-2, 3-DIHYDRO-LH-ISOINDOLE-4-CARBOXAMIDES AS PARP INHIBITORS
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There are provided subs ti tuted 3-ox -2, 3 -dihydro-]H-isoindole-4-carboxamide derivatives (I) which selectively inhibit the activity of poly (ADP-ribose) polymerase PARP- 1 with respect to poly (ADP-ribose) polymerase PARP-2. The compounds of this inven
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Page/Page column 49-50
(2011/02/24)
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