- Synthesis and biological activity of aminoguanidine and diaminoguanidine analogues of the antidiabetic/antiobesity agent 3-guanidinopropionic acid
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3-Guanidinopropionic acid (1) has been demonstrated both to improve insulin sensitivity and to promote weight loss selectively from adipose tissue in animal models of non-insulin-dependent diabetes mellitus (NIDDM). However, 1 has also been shown to be a substrate for both the creatine transporter and creatine kinase, leading to marked accumulation in muscle tissue as the corresponding N-phosphate. The corresponding aminoguanidine analogue 2 was recently discovered to retain the antidiabetic activity of 1 while being markedly less susceptible to creatine-like metabolism, suggesting that it should have less potential to accumulate in muscle. Further structural modification of 2 was undertaken to investigate whether the antidiabetic potency could be augmented while maintaining resistance to creatine-like metabolism. Modifications such as α-alkylation, homologation, and bioisosteric replacement of the aminoguanidine all were detrimental to antidiabetic activity. However, the simple regioisomeric aminoguanidinoacetic acid 9 and diaminoguanidinoacetic acid analogue 7 were found to be equipotent to 2, leading eventually to the discovery of the significantly more potent diaminoguanidinoacetic acid regioisomers 52 and 53. Further attempts to modify the more active template represented by 52 led only to reductions in antidiabetic activity. Each of the new active analogues displayed the same resistance to creatine-like metabolism as 2. Further testing of 7, 9, and 53 in obese diabetic ob / ob mice confirmed that weight loss is induced selectively from adipose tissue, similar to the lead 1. Administration of 53 to insulin-resistant rhesus monkeys led to reductions in both fasting and post-prandial plasma glucose levels with concomitant reductions in plasma insulin levels, suggesting that the compound improved the action of endogenous insulin. Compounds 7 and 53 were selected for further preclinical development.
- Vaillancourt,Larsen,Tanis,Burr,Connell,Cudahy,Evans,Fisher,May,Meglasson,Robinson,Stevens,Tucker,Vidmar,Yu
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p. 1231 - 1248
(2007/10/03)
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- Synthesis and activity of HIV protease inhibitors
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We report here the synthesis and activity of HIV protease inhibitors. In the first stage hydrophobic compounds incorporating a 'carba' bond surrogate or a beta-homologated residue were synthesized. Secondly, we synthesized cyclic compounds in which we incorporated 2-quinoline carboxylic acid in the P3 position and the amino-hydroxyindane moiety in the P'3. The last part of this work was dedicated to a structure/activity study of a peptide substrate. These modifications allowed us to work up the synthesis of new pseudopeptide bonds: amino-amide and hydroxy-amide. Compounds with activity in the micromolar range were actually a starting point for the synthesis of new protease inhibitors.
- Garrouste, Patrick,Pawlowski, Macek,Tonnaire, Thierry,Sicsic, Sames,Dumy, Pascal,De Rosny, Eve,Reboud-Ravaux, Michele,Fulcrand, Pierre,Martinez, Jean
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p. 423 - 436
(2007/10/03)
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- Synthesis and structure of AzAsx-pro-containing Aza-peptides
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One possible α-modification in peptides is the substitution of a nitrogen for the CαH group. We propose triphosgene as a carbonylating agent for coupling the properly substituted hydrazide to the proline nitrogen to obtain the AzAsx-Pro or AzAl
- Andre, Frederic,Marraud, Michel,Boussard, Guy,Didierjean, Claude,Aubry, Andre
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p. 183 - 186
(2007/10/02)
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- Hydrazino and N-Amino peptides. Chemical and structural aspects
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The regioselective acylation of the nitrogens in hydrazino acetic acid has been studied to obtain the hydrazide and N-amino amide peptidomimetic groups Their conformational influence on the β-turn structure has also been considered.
- Lecoq, Alain,Marraud, Michel,Aubry, Andre
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p. 2765 - 2768
(2007/10/02)
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