877151-07-0Relevant articles and documents
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
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
, p. 6875 - 6898 (2015/09/22)
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.
NITROGEN-CONTAINING HETEROCYCLIC COMPOUND
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, (2015/11/16)
Provided is a compound having a cholinergic muscarinic M1 receptor positive allosteric modulator activity, and useful as a prophylactic or therapeutic drug for Alzheimer's disease, schizophrenia, pain, sleep disorder and the like. The present invention relates to a compound represented by the formula wherein ring A is a 4- to 7-membered ring optionally having substituent (s) ; L is -O-, -S-, -SO- or -SO2-; R1 is a C1-6 alkyl group optionally having substituent(s) (provided that when L is -O-, R1 is not a C1-6 alkyl group optionally substituted by halogen atom(s)), or a cyclic group optionally having substituent(s); X1 is -CRa= or -N=; X2 is -CRb= or -N=; X3 is-CRc= or -N=; Ra, Rb and Rc are each a C1-6 alkyl group, C2-6 alkenyl group, C1-6 alkoxy group, C3-6 cycloalkyl group, C3-6 cycloalkoxy group or C6-14 aryl group, each of which optionally having substituent(s), H or halogen, or a salt thereof.
4-CARBOXAMIDO-ISOINDOLINONE DERIVATIVES AS SELECTIVE PARP-1 INHIBITORS
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Page/Page column 30, (2014/05/24)
There are provided substituted 4-carboxamido-isoindolinone derivatives 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 invention are therefore useful in treating diseases such as cancer, cardiovascular diseases, central nervous system injury and different forms of inflammation. The present invention also provides methods for preparing these compounds, pharmaceutical compositions comprising these compounds, and methods of treating diseases utilizing pharmaceutical compositions comprising these compounds
3-0X0-2, 3, -DIHYDRO-LH-ISOINDOLE-4-CARBOXAMIDES WITH SELECTIVE PARP-1 INHIBITION
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Page/Page column 54-55, (2011/02/24)
There are provided substituted 3 -oxo - 2, 3 -dihydro- 1H-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 invention are therefore useful in treating diseases such as cancer, cardiovascular diseases, central nervous system injury and different forms of inflammation. The present invention also provides methods for preparing these compounds, pharmaceutical compositions comprising these compounds, and methods of treating diseases utilizing pharmaceutical compositions comprising these compounds.
3-OXO-2, 3-DIHYDRO-LH-ISOINDOLE-4-CARBOXAMIDES AS PARP INHIBITORS
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Page/Page column 49, (2011/02/24)
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
