A small series of compounds is described in which a narrow SAR has identified N,N-dimethyl-3,4-diphenyl-1H-pyrazole-1-propanamine, 3, as a potential antidepressant with reduced side effects. The isomeric N,N-dimethyl-4,5-diphenyl-1H-pyrazole-1-propanamine was completely inactive in the primary antidepressant screens. Compounds were synthesized by Michael addition of acrylonitrile to diphenylpyrazole followed by reductive alkylation of the resultant diphenylpyrazolepropionitriles. Compound 3 was equipotent with imipramine in standard antidepressant assays in animals but showed no significant anticholinergic action and did not antagonize the antihypertensive effects of clonidine and guanethidine.

Novel glycopeptide analogs are known that have activity on vancomycin resistant enterococci despite the fact that the primary site for drug interaction, D-ala-D-ala, is replaced with D-ala-D-lactate. The mechanism of action of these compounds may involve dimerization and/or membrane binding, thus enhancing interaction with D-ala-D-lactate, or a direct interaction with the transglycosylase enzymes involved in peptidoglycan polymerization. We evaluated the ability of vancomycin (V), desleucyl-vancomycin (desleucyl-V), chlorobiphenyl-vancomycin (CBP-V), and chlorobiphenyl-desleucyl-vancomycin (CBP-desleucyl-V) to inhibit (a) peptidoglycan synthesis in vitro using UDP-muramyl-pentapeptide and UDP-muramyl-tetrapeptide substrates and (b) growth and peptidoglycan synthesis in vancomycin resistant enterococci. Compared to V or CBP-V, CBP-desleucyl-V retained equivalent potency in these assays, whereas desleucyl-V was inactive. In addition, CBP-desleucyl-V caused accumulation of N-acetylglucosamine-beta-1, 4-MurNAc-pentapeptide-pyrophosphoryl-undecaprenol (lipid II). These data show that CBP-desleucyl-V inhibits peptidoglycan synthesis at the transglycosylation stage in the absence of binding to dipeptide.

No abstract

We report the synthesis and in vitro biological activity of the nonpeptide bradykinin receptor antagonist WIN 64338, [[4-[[2-[[bis(cyclohexylamino) Bradykinin (Arg-Pro-Pro-Gly-Phe-Ser-Pro-Phe-Arg) is a nonapeptide released from kininogens by the actions of plasma kallikreins (1) that has been implicated in a variety of physiological and pathological processes, including pain, inflammation, and regulation of blood pressure (2, 3). The effects of bradykinin are mediated through specific G-protein-coupled cell surface receptors (4). These receptors have been tentatively divided into at least three classes, B1, B2, and B3 (5-7), on the basis of pharmacological characterization with selective bradykinin peptide agonists and antagonists. Bradykinin binds to most putative B2 receptors with an affinity in the low nanomolar range under physiological conditions (8).A bradykinin analogue in which D-phenylalanine replaces L-proline in the 7 position of the native ligand was discovered by Vavrek and Stewart (9) and was found to be a bradykinin B2 receptor antagonist. A series of peptide analogues of bradykinin containing this substitution have demonstrated antagonist activity in a variety of tissues (10, 11). The D-Phe7-substituted bradykinin analogues were critical for initial receptor classification; however, they are generally of low potency in various biological assays and demonstrate partial or full agonist activity in certain tissues (12). In addition, these compounds are substrates for carboxypeptidase N (13). Cleavage of the C-terminal arginine by carboxypeptidase N results in compounds that are inactive at the bradykinin B2 receptor but active at the bradykinin B1 receptor (14).The structure and pharmacological activity of a different kind of bradykinin antagonist, DArg0-[Hyp3,Thi5,DTic7, Oic8lbradykinin (HOE-140) [Hyp, (4R)-4-hydroxyprolyl;Thi, 3-(2-thienyl)alanyl; DTic, 1,2,3,4-tetrahydroisoquinolin-2-yl-carbonyl; Oic, (3aS,7aS)-octahydroindol-2-yl-carbonylJ, has recently been described (15,16). In a variety of bradykinin assays, this compound acts as a selective B2 receptor antagonist and is at least two orders of magnitude more potent than any ofthe 18). Although HOE-140 appears to be a competitive antagonist of bradykinin at the B2 receptor in some biological assays, it is reported to be noncompetitive in other systems (19,20).Despite the increases in potency and biological activity observed in second-generation bradykinin receptor antagonists, these compounds are all peptides and therefore subject to metabolism and poor bioavailability (21 [[4-[[2-[[bis(cyclohexylamino) 4693The publication costs of this article were defrayed in part by page charge payment. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. §1734 solely to indicate this fact.

Des-(N-methyl-D-leucyl)eremomycin was obtained by Edman degradation of eremomycin. Derivatives with a hydrophobic substituent at the exterior of the molecule were then synthesized, and their antibacterial activities were compared with similar derivatives of eremomycin. Comparison of derivatives of eremomycin containing the n-decyl or p-(p-chlorophenyl)benzyl substituent in the eremosamine moiety (N') and n-decyl or p-(p-chlorophenyl)benzylamides with similar derivatives of eremomycin possessing the damaged peptide core (a defective binding pocket) showed that compounds of both types are almost equally active against glycopeptide-resistant strains of enterococci (GRE), whereas eremomycin derivatives are more active against staphylococci. Hydrophobic 7d-alkylaminomethylated derivatives of eremomycin (9, 10) demonstrated similar antibacterial properties. Since the basic mode of action of glycopeptide antibiotics involves binding to cell wall intermediates terminating in -D-Ala-D-Ala and this interaction is seriously decreased in the hexapeptide derivatives (lacking the critical N-methyl-D-leucine), we suggest that these hydrophobic derivatives may inhibit peptidoglycan synthesis in the absence of dipeptide binding. NMR binding experiments using Ac-D-Ala-D-Ala show that binding constants of these hexapeptide derivativies are decreased in comparison with the corresponding heptapeptides with intact binding pocket. This is in agreement with the decreased biological activity of the hexapeptide derivatives against vancomycin-sensitive strains in comparison with the activity of parent compounds. Binding to the lactate cell wall analogue Ac-D-Ala-D-Lac with decylamide of eremomycin 8 was not observed, demonstrating that the interaction with this target in GRE does not occur. While hydrophobic glycopeptide derivatives retain the ability to inhibit the synthesis of peptidoglycan in manner of natural glycopeptides, biochemical investigation supports the hypothesis that they inhibit the transglycosylase stage of bacterial peptidoglycan biosynthesis even in the absence of dipeptide or depsipeptide binding.