Search

An efficient approach to N, N′-unsymmetrically substituted ureas 9 has been developed through the ammonolysis process of N -Boc protected anilines 7 with amines prompted by 1,5,7-triazabicyclo[4.4.0]dec-5-ene (TBD). Moreover, a convenient protocol for the synthesis of the symmetric N, N'-substituted ureas 12 by one-pot diammonolysis process of Boc 2 O with amines catalyzed by DABCO has also been achieved. With broad substrate scope and mild conditions, these two methods demonstrate practical preparation of both unsymmetrical and symmetrical ureas. [ABSTRACT FROM AUTHOR]

The inhibition of CYP17 to block androgen biosynthesis is a well validated strategy for the treatment of prostate cancer. Herein we reported the design, synthesis and structure–activity relationship (SAR) study for a series of novel 1,2,3,4- tetrahydrobenzo[4,5]thieno[2,3- c ]pyridine derivatives. Some analogs demonstrated a potent inhibition to both rat and human CYP17 protein and reduced testosterone production in human H295R cell line. Some analogs also showed high selectivity against other CYP enzymes such as 3A4, 1A2, 2C9, 2C19 and 2D6, which may limit side effects due to drug-drug interactions. Among these analogs, the most potent compound 9c showed 1.5 fold more potent against rat and human CYP17 protein than that of abiraterone (IC 50 = 16 nM and 20 nM vs. 25 nM and 36 nM respectively). In NCI-H295R cells, the inhibitory effect of compound 9c on testosterone production (52± 2%) was also more potent than that of abiraterone (74± 15%) at the concentration of 1 μM. Further, it was shown that 9c reduced plasma testosterone level in a dose-dependent manner in Sprague-Dawley rats. Thus, analog 9c maybe a potential agent used for the treatment of prostate cancer. [ABSTRACT FROM AUTHOR]

Isocitrate dehydrogenase 1 (IDH1), which catalyzes the conversion of isocitrate to α-ketoglutarate, is one of key enzymes in the tricarboxylic acid cycle (TCA). Hotspot mutation at Arg132 in IDH1 that alters the function of IDH1 by further converting the α-ketoglutarate(α-KG) to 2-hydroxyglutarate (2-HG) have been identified in a variety of cancers. Because the IDH1 mutations occur in a significant portion of gliomas and glioblastomas, it is important that IDH1 inhibitors have to be brain penetrant to treat IDH1-mutant brain tumors. Here we report the efforts to design and synthesize a novel serial of mutant IDH1 inhibitors with improved activity and the blood-brain barrier (BBB) penetration. We show that compound 5 exhibits good brain exposure and potent 2-HG inhibition in a HT1080-derived mouse xenograft model, which makes it a potential preclinical candidate to treat IDH1-mutant brain tumors. Image 1 • A series of 24 new mutant IDH1 inhibitors have been synthesized and tested. • Compound 5 exhibits excellent inhibitory activity both in the enzyme and in cells. • Compound 5 is demonstrated good pharmacodynamics and pharmacokinetics properties. • Compound 5 exhibits higher exposure than AG-120 in the brain and tumor. • Compound 5 is effective in inhibiting 2-HG in HT1080 xenograft tumor samples. [ABSTRACT FROM AUTHOR]