The tandem chain extension aldol reaction used for synthesis of ketomethylene tripeptidomimetics targeting hPEPT1.

The rationale for targeting the human di-/tripeptide transporter hPEPT1 for oral drug delivery has been well established by several drug and prodrug cases. The aim of this study was to synthesize novel ketomethylene modified tripeptidomimetics and to investigate their binding affinity for hPEPT1. Three related tripeptidomimetics of the structure H-Phe-ψ[COCH(2)]-Ser(Bz)-X(aa)-OH were synthesized applying the tandem chain extension aldol reaction, where amino acid derived β-keto imides were stereoselectively converted to α-substituted γ-keto imides.

Design, synthesis, and evaluation of tripeptidic promoieties targeting the intestinal peptide transporter hPEPT1.

The human intestinal proton coupled di/tri-peptide transporter hPEPT1 promotes the oral bioavailability of several drug compounds. The strategy behind the present work is that by linking a suitable di- or tripeptidic promoiety to a drug substance, by a hydrolysable ester bond, it may give rise to a prodrug that targets hPEPT1. 29 tripeptides were designed based on known structural requirements for substrates binding hPEPT1.

Imidazolines as efficacious glucose-dependent stimulators of insulin secretion.

Synthesis of a series of imidazolines with glucose dependent effects on insulin exocytosis from pancreatic beta-cells is reported. Regioisomers and enantiomers were found to exhibit marked differences in exocytotic effects as well as different activities on the K(ATP)-channel; the (R (+)) isomer of 2-[2-(4,5-dihydro-1H-imidazol-2-yl)-1-thiophene-2-ylethyl]pyridine (4a) and the (+) isomer of 2-[2-(4,5-dihydro-1H-imidazol-2-yl)-1-thiophene-3-ylethyl]pyridine (4d) were found to give a significant increase in insulin release-in contrast to findings for their enantiomers-without influence on the K(ATP)-channel. The (+) isomer (4a) showed glucose dependent insulin release from beta-cells at concentrations above 2.

N-Alkoxypyrazoles as biomimetics for the alkoxyphenyl group in tamoxifen.

The preparation of a series of novel analogues of the selective antiestrogen tamoxifen is reported. 1Z-alkoxyphenyl group in tamoxifen has been replaced by a N-alkoxypyrazole, while functionalised phenyl groups or heteroaromatics were introduced at the 2Z-position using sequential Suzuki cross coupling of 1,2-(bis)borylpinacol 1-phenylbutene with 4- or 5-iodo-1-N,N-dimethylaminoethyl or propyl-pyrazoles. Approximately 50 tamoxifen analogues were obtained and tested in an estrogen receptor (ERalpha) affinity assay.

First nucleophilic aromatic substitution of annelated pyrazole.

3-Chloropyrazolo[3,4-c]quinoline 5, 3-chloropyrazolo[3,4-c]isoquinoline 6, 1,2-dihydro-1,2-dimethylpyrazolo[3,4-c]quinolin-3-one 8, and 1,2-dihydro-1,2-dimethylpyrazolo[3,4-c]isoquinolin-3-one 10 were obtained by acid-induced nucleophilic aromatic substitution (S(N)H) of H-3 in N-hydroxypyrazolo[3,4-c]quinoline 1b and in N-hydroxy pyrazolo[3,4-c]isoquinoline 3b. In the acid-induced chlorination, 3b was far more reactive than 1b, whereas the related N-hydroxypyrazolo[4,3-c]quinoline 2b and N-hydroxypyrazolo[4,3-c]isoquinoline 4b were completely unreactive toward S(N)H under identical conditions.