- The metabolism of a series of ester pro-drugs by NCTC 2544 cells, skin homogenate and LDE testskin
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The metabolism of a series of substituted pyrazolopyridine ester pro-drugs was investigated using NCTC 2544 cells, human skin homogenate and LDE Testskin as model systems. The compounds were incubated in each system and the disappearance of drug and the production of the major hydrolysis product was observed with time and quantitated using HPLC. The toxicity of the ester pro-drugs and the metabolites was examined in NCTC 2544 cells using a cell viability assay procedure. Hydrolytic activity was slightly higher in the cell culture model than in skin homogenate solution but the rank order of activity for each pro-drug was similar. The metabolic activity of LDE Testskin was much reduced compared with the other systems, but again the overall pattern of metabolism was not dissimilar. These findings indicate that NCTC 2544 cells provide a reasonable model for human skin ester hydrolysis both in terms of rate and in terms of substrate specificity.
- Lamb,Denyer,Sanderson,Shaw
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- Discovery and characterization of a novel 7-aminopyrazolo[1,5-a]pyrimidine analog as a potent hepatitis C virus inhibitor
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We describe a novel 7-aminopyrazolo[1,5-a]pyrimidine (7-APP) derivative as a potent hepatitis C virus (HCV) inhibitor. A series of 7-APPs was synthesized and evaluated for inhibitory activity against HCV in different cell culture systems. The synthesis and preliminary structure-activity relationship study of 7-APP are reported.
- Hwang, Jong Yeon,Windisch, Marc Peter,Jo, Suyeon,Kim, Keumhyun,Kong, Sunju,Kim, Hyoung Cheul,Kim, Soohyun,Kim, Heeyoung,Lee, Myung Eun,Kim, Youngmi,Choi, Jihyun,Park, Dong-Sik,Park, Eunjung,Kwon, Jeongjin,Nam, Jiyoun,Ahn, Sujin,Cechetto, Jonathan,Kim, Junwon,Liuzzi, Michel,No, Zaesung,Lee, Jinhwa
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p. 7297 - 7301
(2013/02/23)
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- Structure-activity relationship study of bone morphogenetic protein (BMP) signaling inhibitors
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A structure-activity relationship study of dorsomorphin, a previously identified inhibitor of SMAD 1/5/8 phosphorylation by bone morphogenetic protein (BMP) type 1 receptors ALK2, 3, and 6, revealed that increased inhibitory activity could be accomplished by replacing the pendent 4-pyridine ring with 4-quinoline. The activity contributions of various nitrogen atoms in the core pyrazolo[1,5-a]pyrimidine ring were also examined by preparing and evaluating pyrrolo[1,2-a]pyrimidine and pyrazolo[1,5-a]pyridine derivatives. In addition, increased mouse liver microsome stability was achieved by replacing the ether substituent on the pendent phenyl ring with piperazine. Finally, an optimized compound 13 (LDN-193189 or DM-3189) demonstrated moderate pharmacokinetic characteristics (e.g., plasma t1/2 = 1.6 h) following intraperitoneal administration in mice. These studies provide useful molecular probes for examining the in vivo pharmacology of BMP signaling inhibition.
- Cuny, Gregory D.,Yu, Paul B.,Laha, Joydev K.,Xing, Xuechao,Liu, Ji-Feng,Lai, Carol S.,Deng, Donna Y.,Sachidanandan, Chetana,Bloch, Kenneth D.,Peterson, Randall T.
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supporting information; scheme or table
p. 4388 - 4392
(2009/04/06)
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- Pyrazolo[1,5-a]pyrimidines as orally available inhibitors of cyclin-dependent kinase 2
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Properly substituted pyrazolo[1,5-a]pyrimidines are potent and selective CDK2 inhibitors. Compound 15j is orally available and showed efficacy in a mouse A2780 xenograft model.
- Paruch, Kamil,Dwyer, Michael P.,Alvarez, Carmen,Brown, Courtney,Chan, Tin-Yau,Doll, Ronald J.,Keertikar, Kerry,Knutson, Chad,McKittrick, Brian,Rivera, Jocelyn,Rossman, Randall,Tucker, Greg,Fischmann, Thierry O.,Hruza, Alan,Madison, Vincent,Nomeir, Amin A.,Wang, Yaolin,Lees, Emma,Parry, David,Sgambellone, Nicole,Seghezzi, Wolfgang,Schultz, Lesley,Shanahan, Fran,Wiswell, Derek,Xu, Xiaoying,Zhou, Quiao,James, Ray A.,Paradkar, Vidyadhar M.,Park, Haengsoon,Rokosz, Laura R.,Stauffer, Tara M.,Guzi, Timothy J.
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p. 6220 - 6223
(2008/03/18)
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- NITROAZINES. 15. CONTRACTION OF THE PYRIMIDINE RING IN 6-NITROAZOLOPYRIMIDINES
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It is shown that contraction of the pyrimidine ring occurs when 6-nitro-7-oxo-4,7-dihydroazolopyrimidines are heated with hydrazine hydrate.Complexes of 4-nitropyrazole with 5-aminoazoles, the structures of which were proved by x-ray diffraction analysis, are formed in a similar reaction of nitrosubstituted azolopyrimidines that do not contain an oxo function.
- Rusinov, V. L.,Myasnikov, A. V.,Chupakhin, O. N.,Aleksandrov, G. G.
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p. 530 - 533
(2007/10/02)
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- Rearrangement of 1-Amino- and 1-Alkylamino-pyrazoles to 5-Aminopyrazoles
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Rearrangement of 1-aminopyrazole and 1-alkylaminopyrazoles into the corresponding 5-aminopyrazoles has been achieved in 48percent aqueous hydrobromic acid.The reaction, occurring through a ring opening-ring closure mechanism, constitutes a new and unambiguous procedure for the preparation of 1-substituted 5-aminopyrazoles.The products have been identified on the basis of 1H and 13C n.m.r. spectroscopic results and comparison with authentic samples.
- Sanz, Dionisia,Claramunt, Rosa Ma.,Elguero, Jose,Salazar, Loreto,Espada, Modesta
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p. 809 - 810
(2007/10/02)
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