Phthalazinone Pyrazoles as Potent, Selective, and Orally Bioavailable Inhibitors of Aurora-A Kinase

Abstract

The inhibition of Aurora kinases in order to arrest mitosis and subsequently inhibit tumor growth via apoptosis of proliferating cells has generated significant discussion within the literature. We report a novel class of Aurora kinase inhibitors based upon a phthalazinone pyrazole scaffold. The development of the phthalazinone template resulted in a potent Aurora-A selective series of compounds (typically >1000-fold selectivity over Aurora-B) that display good pharmacological profiles with significantly improved oral bioavailability compared to the well studied Aurora inhibitor VX-680.

Convenient Synthesis of Some Novel 4-Benzyl-1(2<em>H</em>)-Phthalazinone Derivatives of expected anticancer activity

“…A series of 4-substituted-2H-phthalazin-1-ones have been investigated as potent orally bioavailable PARP (poly (adenosine diphosphate-ribose) polymerases) inhibitor [19][20][21][22][23][24][25][26] Olaparib I, MRU-868 II and KU0058958 III are the most interesting PARP inhibitors based on the 4-substituted-2H-phthalazin-1-one scaffold and compound IV inhibits aurora-A kinase based upon a 4-(pyrazole-3ylamino)phenyl-2H-phthalazin-1-one scaffold and has in vitro cytotoxic activity against HCT116 colon cell line 27 , these commercial phthalazinone derivatives are shown in figure 1 . We will present new compound designs from N-substituted phthalazin-1-one derivatives based on the 4-benzylphthalazin-1-one scaffold in an attempt to obtain a potent anticancer agent.…”

Targeting the BCL2 Gene Promoter G‐Quadruplex with a New Class of Furopyridazinone‐Based Molecules

“…In particular,w ed esigneda nd synthesized as mall series of furopyridazinone-based molecules. The pyridazinone nucleusw as selected because it is present in a plethora of compounds endowed with variousbiologicalactivities (antihypertensive, antithrombotic, anti-inflammatory,a nd anticancer), [16,17] and it is considered ap rivileged structure that is currently experiencingarenewed interest in medicinal chemistry.S tartingf rom this nucleus, we recently presented an expeditiousm ulticomponent one-potr eaction methodology for generating as mall collection of fully substituted furo[2,3d]pyridazin-4(5H)-ones (FPs). [18,19] The facile and efficient synthetic route for the FP derivatives is shown in Scheme 1.…”

Design and Synthesis of New Phthalazinone Derivatives Containing Benzyl Moiety with Anticipated Antitumor Activity

“…Interestingly, Prime et al 28) have reported a novel class of potent, selective, and orally bioavailable inhibitors of aurora-A kinase based upon a 4-(pyrazole-3-ylamino) phenyl-2H-phthalazin-1-one scaffold. Compound (IV) inhibits aurora-A with IC 50 of 71 nM, also, it showed in vitro cytotoxic activity against HCT116 colon cell line with IC 50 of 5.44 nM.…”