s other disease associated with disturbed liver function, alcohol or illicit drug abuse, and previous consumption of prescriptionfree synthetic drugs or herbal medicines as possible alternative causes of current liver disease. VX-680 MK-0457 Third, serological testing for viral etiology of liver disease was negative. Fourth, serological testing for an autoimmune disorder possibly underlying the hepatitis was also negative. Fifth, repeated ultrasonography and MRT investigations did not indicate any other alternative explanation of liver injury, such as mechanical bile duct obstruction. Furthermore there was no evidence of hemolysis that could explain the increased bilirubin serum levels. Before developing hepatitis, the patient received TZM as a component of the radiochemotherapy regime.
Additionally, he received a low dose of dexamethasone and pantoprazole. Incidentally, this drug treatment was completed the day before the onset of clinical symptoms. The cholestatic hepatitis had a sustained course over more than 6 months and the liver pathology was clearly consistent with toxic liver injury, confirming the possibility of drug etiology. The temporal pattern of serum parameters was interpreted as initial hepatocellular damage, which was followed by sustained cholestatic liver disease. The Drug Commission of the German Medical Association published another case of TZM associated cholestatic hepatitis and sustained hepatotoxicity that was reported to its spontaneous reporting system.7 This case concerned a 67 year old male with a rightcentral GBM.
After surgery and the start of a radiochemotherapy regime with TZM, the patient developed jaundice, a 3 fold elevation of AST, a 10 fold elevation of ALT, a 9 fold elevation of gamma glutamyl transferase, and a bilirubin level of 11.1 mg/dL. TZM was discontinued, as the possible cause of this liver injury. Despite TZM discontinuation, the level of bilirubin continued to increase up to 24 mg/dL. The patient developed hepatic failure with encephalopathy and eventually died. A search for further cases of hepatotoxicity associated with TZM in the PubMed and Embase databases identified 7 cases,8 14 of which 2 were considered not causally related to TZM but to other drug treatment given concomitantly with TZM.
9,13 Among the 5 cases thought to be causally related to TZM, one published by Goldbecker and colleagues10 concerned a 66 year old woman who developed severe cholestatic liver damage after 27 cycles of radiation combined with continuous TZM treatment for GBM. At the start of radiochemotherapy in August 2007, liver enzymes were in the normal range. In October 2007 the patient developedminimum of four steps, making library synthesis quite laborious. As such, we envisaged a late stage Suzuki coupling of commercially available boronic acids to the 3 bromothiophene intermediate allowing for rapid access to a variety of analogues at the 3 position as shown in Scheme 2. Reaction of N 4 piperidone with ethyl 2 cyanoacetate using the conditions described above, followed by acetylation and subsequent saponification of the formed ethyl ester, gave the desired 3 COOH intermediate 9a. Decarboxylation using dimethylacetamide at 170 for 2 h in a microwave gave the des carboxy product 10a after optimization of the reaction conditio