- 3,4,5-TRISUBSTITUTED-1,2,4-TRIAZOLES AND 3,4,5-TRISUBSTITUTED-3-THIO-1,2,4-TRIAZOLES AND USES THEREOF
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The present disclosure describes novel compounds that are somatostatin receptor type 4 agonists.
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- BIARYL MONOBACTAM COMPOUNDS AND METHODS OF USE THEREOF FOR THE TREATMENT OF BACTERIAL INFECTIONS
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The present invention relates to biaryl monobactam compounds of Formula I: and pharmaceutically acceptable salts thereof, wherein X, Y, Z, A1, Q, A2, M, W, RX and Rz are as defined herein. The present invention also relates to compositions which comprise a biaryl monobactam compound of the invention or a pharmaceutically acceptable salt therof, and a pharmaceutically acceptable carrier. The invention further relates to methods for treating a bacterial infection comprising administering to the patient a therapeutically effective amount of a compound of the invention, either alone or in combination with a therapeutically effective amount of a second beta-lactam antibiotic.
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- DOUBLE-ACYLATED GLP-1 DERIVATIVES
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The invention relates to a derivative of a GLP-1 analogue, which analogue comprises a first K residue at a position corresponding to position 37 of GLP-1 (7-37) (SEQ ID NO: 1), a second K residue at a position corresponding to position 26 of GLP-1 (7-37), and a maximum of ten amino acid modifications as compared to GLP-1 (7-37), wherein the first K residue is designated K37, and the second K residue is designated K26, which derivative comprises two albumin binding moieties attached to K26 and K37, respectively, wherein the albumin binding moiety comprises a protracting moiety selected from: ????????Chem. 1:?????HOOC-(CH2)x-CO-* ????????Chem. 2:?????HOOC-C6H4-O-(CH2)y-CO-* ????????Chem. 3:?????R1-C6H4-(CH2)z-CO-* ????????Chem. 4:?????HOOC-C4SH2-(CH2)w-CO-* in which x is an integer in the range of 6-18, y is an integer in the range of 3-17, z is an integer in the range of 1-5, R1 is a group having a molar mass not higher than 150 Da, and w is an integer in the range of 6-18; with the proviso that when the protracting moiety is Chem. 1, the albumin binding moiety further comprises a linker of formula Chem. 5: *-NH-(CH2)2-(O-(CH2)2)k-O-(CH2)n-CO-*, wherein k is an integer in the range of 1-5, and n is an integer in the range of 1-5; or a pharmaceutically acceptable salt, amide, or ester thereof. The invention also relates to the pharmaceutical use thereof, for example in the treatment and/or prevention of all forms of diabetes and related diseases, as well as to corresponding novel peptides and side chain intermediates. The derivatives are suitable for oral administration.
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- Ng-acylated imidazolylpropylguanidines as potent histamine H4 receptor agonists: selectivity by variation of the n g-substituent?
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3-(1H-Imidazol-4-yl)propylguanidine (SK&F 91486, 4) was identified as a potent partial agonist at the human histamine H3 receptor (hH3R) and human histamine H4 receptor (hH4R). With the aim to increase selectivity for the
- Igel, Patrick,Schneider, Erich,Schnell, David,Elz, Sigurd,Seifert, Roland,Buschauer, Armin
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supporting information; experimental part
p. 2623 - 2627
(2010/03/24)
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- Synthesis and structure-activity relationships of cyanoguanidine-type and structurally related histamine H4 receptor agonists
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Recently, we identified high-affinity human histamine H3 (hH3R) and H4 receptor (hH4R) ligands among a series of NG-acylated imidazolylpropylguanidines, which were originally designed as histamine H2 receptor (H2R) agonists. Aiming at selectivity for hH4R, the acylguanidine group was replaced with related moieties. Within a series of cyanoguanidines, 2-cyano-1-[4-(1H-imidazol-4-yl)butyl]-3-[(2-phenylthio)ethyl]guanidine (UR-PI376, 67) was identified as the most potent hH4R agonist (pEC50=7.47, α=0.93) showing negligible hH1R and hH2R activities and significant selectivity over the hH3R (pKB=6.00, α=-0.28), as determined in steady-state GTPase assays using membrane preparations of hHxR-expressing Sf9 cells. In contrast to previously described selective H4R agonists, this compound and other 3-substituted derivatives are devoid of agonistic activity at the other HR subtypes. Modeling of the binding mode of 67 suggests that the cyanoguanidine moiety forms chargeassisted hydrogen bonds not only with the conserved Asp-94 but also with the hH4R-specific Arg-341 residue. 2-Carbamoyl-1-[2-(1H-imidazol-4-yl)ethyl]-3-(3-phenylpropyl)guanidine (UR-PI97, 88) was unexpectedly identified as a highly potent and selective hH3R inverse agonist (pKB=8.42, >300-fold selectivity over the other HR subtypes). 2009 American Chemical Society.
- Igel, Patrick,Geyer, Roland,Strasser, Andrea,Dove, Stefan,Seifert, Roland,Buschauer, Armin
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supporting information; experimental part
p. 6297 - 6313
(2010/03/24)
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- PIPERAZINE DERIVATIVES AS FARNESYL PROTEIN TRANSFERASE INHIBITORS
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Disclosed are compounds of the formula: wherein R13 represents an imidazole ring; R14 represents a carbamate, urea, amide or sulfonamide group, and the remaining substituents are as defined herein. Also disclosed is a method of treating cancer and a method of inhibiting farnesyl protein transferase using the disclosed compounds.
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Page/Page column 205
(2010/11/28)
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- [3-(1H-Imidazol-4-yl)propyl]guanidines containing furoxan moieties: A new class of H3-antagonists endowed with NO-donor properties
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Synthesis and pharmacological characterisation of a series of products obtained by coupling the H3-antagonist SKF 91486 through appropriate spacers with the NO-donor 3-phenylfuroxan-4-yloxy and 3-benzenesulfonylfuroxan-4-yloxy moieties, as well as with the corresponding furazan substructures, devoid of NO-donating properties, are reported. All the products were tested for their H3-antagonistic and H2-agonistic properties on electrically-stimulated guinea-pig ileum segments and guinea-pig papillary muscle, respectively. The whole series of compounds displayed good H3-antagonist behaviour and feeble partial H2-agonist activity. Among furoxan derivatives, the benzenesulfonyl hybrid 28, a good NO-donor, triggered a dual NO-dependent muscle relaxation and H3-antagonistic effect on guinea-pig intestine.
- Bertinaria, Massimo,Di Stilo, Antonella,Tosco, Paolo,Sorba, Giovanni,Poli, Enzo,Pozzoli, Cristina,Coruzzi, Gabriella,Fruttero, Roberta,Gasco, Alberto
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p. 1197 - 1205
(2007/10/03)
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- H3 receptor ligands: New imidazole H3-antagonists endowed with NO-donor properties
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Synthesis and pharmacological properties of a group of compounds obtained by coupling the H3-antagonist SKF 91486 with the NO-donor 3-phenylfuroxan-4-yloxy and 3-benzenesulfonylfuroxan-4-yloxy moieties, as well as with the corresponding furazan analogues, devoid of NO-donating properties, are reported. All the products were tested for their H3-antagonistic and H2-agonistic properties on electrically-simulated guinea-pig ileum segments and guinea-pig papillary muscle, respectively. All the synthesised compounds displayed good H3-antagonistic properties (pA2 range 7.02-8.49) while behaving only as weak partial H2-agonists. Derivative 28, the best NO-donor of the series, was able to trigger a dual NO-dependent muscle relaxation and H3-antagonistic effect on guinea-pig illeum.
- Bertinaria, Massimo
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p. 279 - 283
(2007/10/03)
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- Imidazole derivatives as a novel class of hybrid compounds with inhibitory histamine N-methyltransferase potencies and histamine hH3 receptor affinities
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In this study, a novel series of imidazole-containing compounds with dual properties, that is, inhibitory potency at the enzyme histamine Nτ-methyltransferase (HMT) and antagonist potency at histamine H3 receptors was designed and sy
- Grassmann, Sven,Apelt, Joachim,Sippl, Wolfgang,Ligneau, Xavier,Pertz, Heinz H.,Zhao, Yuan Hui,Arrang, Jean-Michel,Ganellin, C. Robin,Schwartz, Jean-Charles,Schunack, Walter,Stark, Holger
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p. 2163 - 2174
(2007/10/03)
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- Sulfonamides and sulfamides as H3 receptor antagonists
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PCT No. PCT/GB97/00358 Sec. 371 Date Oct. 6, 1998 Sec. 102(e) Date Oct. 6, 1998 PCT Filed Feb. 10, 1997 PCT Pub. No. WO97/29092 PCT Pub. Date Aug. 14, 1997Compounds of formula (I) or (II) wherein R1 is C4 to C20 hydrocarbyl (in which one or more hydrogen atoms may be replaced by halogen, and up to three carbon atoms may be replaced by oxygen, nitrogen or sulphur atoms, provided that R1 does not contain an -O-O- group), R2 is H or C1 to C3 alkyl, m is from 1 to 15, n is from 2 to 6, each X group is independently (a), or one X group is -N(R4)-, -O- or -S- and the remaining X groups are independently (a), wherein R3 is H, C1 to C6 alkyl, -CO2R5, -CONR52, -CR52OR6 or -OR5 (in which R5 and R6 are H or C1 to C3 alkyl), and R4 is H or C1 to C6 alkyl, each Y group is independently -C(R3)R4-, or up to two Y groups are -N(R4)-, -O- or -S- and the remaining Y groups are independently -C(R3)R4-, wherein R3 is as defined above, one R4 group in the structure is imidazoyl or imidazoylalkyl and the remaining R4 groups are H or C1 to C6 alkyl, and Z is >C(R7)NR2- or >N-, wherein R7 is any of the groups recited above for R3, and pharmaceutically acceptable salts thereof are ligands at histamine H3 receptors.
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- Discovery of a novel non-peptide somatostatin agonist with SST4 selectivity
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The discovery of novel non-peptide compounds with a high affinity for the peptide hormone somatostatin (SST) receptor is described. The compounds were tested for affinity at five human SST receptor subtypes individually expressed in mammalian cells. The c
- Ankersen, Michael,Crider, Michael,Liu, Shengquan,Ho, Bin,Andersen, Henrik S.,Stidsen, Carsten
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p. 1368 - 1373
(2007/10/03)
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- Novel H3 receptor antagonists. Sulfonamide homologs of histamine.
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Sulfonamides derived from 4(5)-(omega-aminoalkyl)-1H-imidazoles containing chain lengths of three- to five-carbons were synthesized. Good to moderate H3 receptor binding affinities were observed for several butyl and pentyl homologs, whereas binding affinities were considerably weaker in the propyl series. Separation of the imidazole ring and the sulfonamide unit by a four- or five-carbon tether afforded potent H3 receptor antagonists.
- Wolin,Connolly,Afonso,Hey,She,Rivelli,Willams,West Jr.
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p. 2157 - 2162
(2007/10/03)
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