Detail of "83345-46-4"

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Potent and systemically active aminopeptidase N inhibitors designed from active-site investigation

Potent and systemically active aminopeptidase N inhibitors designed from active-site investigation. Fournie-Zaluski, Marie Claude; Coric, Pascale; Turcaud, Serge; Bruetschy, Luce; Lucas, Evelyne; Noble, Florence; Roques, Bernard P. (Dep. Chim. Org., Univ. Rene Descartes, Paris 75270, Fr.). J. Med. Chem., 35(7), 1259-66 (English) 1992. CODEN: JMCMAR. ISSN: 0022-2623. DOCUMENT TYPE: Journal CA Section: 34 (Amino Acids, Peptides, and Proteins) Section cross-reference(s): 1 Derivs. of amino acids bearing various zinc-coordinating moieties e.g. H2NCHRCH2R1 [R = CH2Ph, CH2C6H4OH-4, 2-naphthylmethyl, cyclohexylmethyl, CH2OCH2Ph, CH2SCH2Ph, CH2CHMe2, CH2CH2SMe, CH2SMe, CH2SCMe3, CH2S(O)Me, CH2CH2S(O)Me; R1 = SH, CO2H, CONHOH, PO3H2] were synthesized and tested for their ability to inhibit aminopeptidase N (I). Among them, b-amino thiols were the most efficient with ED50 = 11-50 nM. These results suggest that the S1 subsite of I is a deep but not very large hydrophobic pocket, optimally fitting side chains of moderate bulk endowed with some degree of freedom. The i.v. administration of the inhibitors, alone, did not induce antinociceptive responses in the hot plate test in mice. However, in presence of 10 mg/kg acetorphan, a prodrug of the neutral endopeptidase inhibitor thiorphan, these compds.In this experiment, several chemicals are used like 139428-71-0 and 83345-46-4 gave a large increase in the jump latency time with ED50 = 2 and 2.4 mg/kg for (H2NCHRCH2S)2 [R = CH2CH2SMe, CH2CH2S(O)Me], resp. These results show that the disulfide forms of b-amino thiols are efficient prodrugs of aminopeptidase N inhibitors capable of crossing the blood-brain barrier. .