Mavunkel B J, Lu Z, Goehring R R, Lu S, Chakravarty S, Perumattam J, Novotny E A, Connolly M, Valentine H, Kyle D J
Scios Nova, Inc., Sunnyvale, California 94086, USA.
J Med Chem. 1996 Aug 2;39(16):3169-73. doi: 10.1021/jm950676i.
A series of pseudopeptides containing alkyl-, cycloalkyl-, aryl-, and aralkyl-substituted 1,3,8-triazaspiro[4.5]decan-4-one-3-acetic acids as amino acid surrogates to replace the Pro2-Pro3-Gly4-Phe5 section of the peptide bradykinin B2 receptor antagonist [Pro3, Phe5]HOE 140 (D-Arg0-Arg1-Pro2-Pro3-Gly4-Phe5-Ser6-D-Tic7+ ++-Oic8-Arg9) were prepared. These psuedopeptides were examined in vitro for their B2 receptor affinities as well as for their ability to block bradykinin mediated actions in vivo. Two compounds in particular, NPC 18521 (I) and NPC 18688 (V) were quite potent in these latter assays, indicating that a significant portion of this prototypical second generation decapeptide antagonist can be replaced with a more compact nonpeptide molecule.
制备了一系列含有烷基、环烷基、芳基和芳烷基取代的1,3,8-三氮杂螺[4.5]癸烷-4-酮-3-乙酸的假肽，作为氨基酸替代物来取代肽缓激肽B2受体拮抗剂[Pro3, Phe5]HOE 140（D-Arg0-Arg1-Pro2-Pro3-Gly4-Phe5-Ser6-D-Tic7- - -Oic8-Arg9）的Pro2-Pro3-Gly4-Phe5片段。对这些假肽进行了体外B2受体亲和力检测以及体内阻断缓激肽介导作用的能力检测。特别是两种化合物NPC 18521（I）和NPC 18688（V）在这些后期检测中表现出相当强的活性，表明这种典型的第二代十肽拮抗剂的很大一部分可以被更紧凑的非肽分子取代。
