The current situation of chiral drug development in Japan was investigated. The trend in the Japanese pharmaceutical development is increasingly moving towards the development of single isomers rather than racemates. The development of single-enantiomer drugs was made possible by the current technologies of asymmetric synthesis and chiral separation, and encouraged by the guidelines on the development of chiral drugs worldwide. Japan has not issued specific guidelines on the development of chiral drugs, however, the chiral drug development approached in Japan were essentially consistent with the approaches recommended by the U.S.A. and EU guidelines.
Substantial differences in safety information exist depending upon outcome measures and therapeutic areas among the US, the UK, and the Japanese labels. This underscores the need for further analyses to determine causes of these differences to optimize drug safety regulations.
Yeast fatty-acid synthase (FAS) inhibition by cerulenin analogs with varying side-chain lengths was compared with that of cerulenin, tetrahydrocerulenin and iodoacetamide. Although inhibition by cerulenin was the highest, the analogs having (E,E)-A'*" double bonds showed high inhibition. This strongly suggests that the (E, E)-d7? l o double bonds play an important role in the interaction of the inhibitors with the enzyme. It was suggested that the size of the hydrophobic cavity in the condensing enzyme terminates fatty-acid chain elongation by decreasing inhibition by the C1 analog. Like cerulenin itself, the shortest analog (C,) did not induce malonyl-CoA decarboxylase activity.Cerulenin 1 [I, 21 is an antibiotic produced by Cephalosporium caerulens [3]. It has a hydrophilic head part (C1 -C4) with a cis-epoxide moiety and a hydrophobic side chain with an (E,E)-lP-diene system (C5-Cl2) [4, 51 (Fig. 1).Cerulenin inhibits fatty-acid synthase (FAS) [6] of both multifunctional and unassociated enzymes [7 -111, except the synthase from cerulenin-producing fungi [12-141. Vance et al.[15] first reported, using the enzyme preparation from Mycobacterium phlei, that 3-oxoacyl synthase (condensing enzyme) was hghly sensitive to cerulenin. Subsequently, d'Agnelo et al. [16] confirmed, with the purified enzyme from Escherichia coli, that cerulenin binds to the cysteine at the active site of the condensing enzyme (active cysteine thiol group) and inhibits the condensation of fatty-acylated acylcarrier protein (ACP) and malonyl-ACP. They observed that inhibition of the condensing enzyme by cerulenin was irreversible, and that the molar ratio of cerulenin/enzyme was approximately 1 : 1 when inhibition approached 100%.Inhibition of FAS by cerulenin is more potent and specific [7] than that by the thiol inhibitor iodoacetamide (4), which binds to the same cysteine residue [17-191. This was demonstrated by comparison of the second-order rate constants (k,) of the reactions. The values of the rate constant k, were 88 M-' . S-' [7] and 1.0 M-' . S- ' [19] for the reaction between cerulenin and yeast FAS, and between iodoacetamide and FAS, respectively. These data indicate that yeast FAS reacts with cerulenin about 90 times faster than with iodoacetamide [7].We have already demonstrated that cerulenin reacts with the cysteine thiol group at C2 to give the adduct 2b (Fig. 1) in a model reaction between cerulenin and cysteine methyl
Abstract. Polycyclic aromatic hydrocarbons (PAHs) and dioxins are ubiquitous environmental pollutants and activate the aryl hydrocarbon receptor (AhR), a ligand-activated transcription factor. It has been reported that testosterone represses 2,3,7,8-tetrachlorodibenzo-p-dioxininduced transcription of the cytochrome P450 (CYP) 1A1 gene in LNCaP cells. In this study, we investigated the mechanism for the repression of 3-methylcholanthrene (3MC)-induced transcription of AhR-regulated genes, CYP1A1, CYP1A2, CYP1B1, and AhR repressor (AhRR), by 5α-dihydroteststerone (DHT) in LNCaP and T47D cells, which are androgen receptor (AR)-and AhR-positive. Real-time PCR analysis showed that DHT repressed 3MC-induced mRNA expression of the CYP1 family and AhRR genes. DHT repressed 3MC-induced luciferase activity in an AhR response element-driven luciferase reporter assay in LNCaP and T47D cells. The inhibitory effect of DHT was abolished by knockdown of AR protein with siRNA. The protein levels of AhR and AhR nuclear translocator (Arnt), the AhR-dimerizing partner, were not affected by DHT. Co-immunoprecipitation assay showed that DHT significantly facilitated the complex formation between AR and AhR in 3MC-treated cells. These results suggest that complex formation between activated AR and AhR plays an important role in the suppression of 3MC-induced transcription of CYP1 family genes by DHT.
A novel series of small molecule nonpeptide aminopeptidase N (APN) inhibitors with a N-phenylphthalimide or N-phenylhomophthalimide skeleton were prepared. Evaluation of their protease inhibitory activities revealed that (i) some N-phenylphthalimide analogs are potent APN inhibitors, but they are also inhibitors of another protease, dipeptidylpeptidase IV (DPP-IV), and (ii) some N-phenylhomophthalimide analogs, including 2-(2,6-diethylphenyl)-1,2,3,4-tetrahydroisoquinoline-1,3-dione (PIQ-22), are potent and specific inhibitors of APN without DPP-IV-inhibitory activity. The structure-activity relationship studies of N-phenylphthalimides and N-phenylhomophthalimides are reviewed. PIQ-22 showed potent tumor-cell invasion-inhibitory activity.
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