Discovery of 2-{4-[(3S)-Piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide (MK-4827): A Novel Oral Poly(ADP-ribose)polymerase (PARP) Inhibitor Efficacious in BRCA-1 and -2 Mutant Tumors was written by Jones, Philip;Altamura, Sergio;Boueres, Julia;Ferrigno, Federica;Fonsi, Massimiliano;Giomini, Claudia;Lamartina, Stefania;Monteagudo, Edith;Ontoria, Jesus M.;Orsale, Maria Vittoria;Palumbi, Maria Cecilia;Pesci, Silvia;Roscilli, Giuseppe;Scarpelli, Rita;Schultz-Fademrecht, Carsten;Toniatti, Carlo;Rowley, Michael. And the article was included in Journal of Medicinal Chemistry in 2009.Category: esters-buliding-blocks This article mentions the following:
We disclose the development of a novel series of 2-phenyl-2H-indazole-7-carboxamides as poly(ADP-ribose)polymerase (PARP) 1 and 2 inhibitors. This series was optimized to improve enzyme and cellular activity, and the resulting PARP inhibitors display antiproliferation activities against BRCA-1 and BRCA-2 deficient cancer cells, with high selectivity over BRCA proficient cells. Extrahepatic oxidation by CYP450 1A1 and 1A2 was identified as a metabolic concern, and strategies to improve pharmacokinetic properties are reported. These efforts culminated in the identification of 2-{4-[(3S)-piperidin-3-yl]phenyl}-2H-indazole-7-carboxamide (MK-4827), which displays good pharmacokinetic properties and is currently in phase I clin. trials. This compound displays excellent PARP 1 and 2 inhibition with IC50 = 3.8 and 2.1 nM, resp., and in a whole cell assay, it inhibited PARP activity with EC50 = 4 nM and inhibited proliferation of cancer cells with mutant BRCA-1 and BRCA-2 with CC50 in the 10-100 nM range. MK-4827 was well tolerated in vivo and demonstrated efficacy as a single agent in a xenograft model of BRCA-1 deficient cancer. In the experiment, the researchers used many compounds, for example, Methyl 2-aminonicotinate (cas: 14667-47-1Category: esters-buliding-blocks).
Methyl 2-aminonicotinate (cas: 14667-47-1) belongs to esters. Esters perform as high-grade solvents for a broad array of plastics, plasticizers, resins, and lacquers, and are one of the largest classes of synthetic lubricants on the commercial market. Polyesters are important plastics, with monomers linked by ester moieties. Esters are more polar than ethers but less polar than alcohols. They participate in hydrogen bonds as hydrogen-bond acceptors, but cannot act as hydrogen-bond donors, unlike their parent alcohols. This ability to participate in hydrogen bonding confers some water-solubility.Category: esters-buliding-blocks
Referemce:
Ester – Wikipedia,
Ester – an overview | ScienceDirect Topics