ABSTRACT
Ligand-biased receptor signaling has been proposed for several G-protein coupled receptors including the niacin receptor GPR109A. Coupling to the G(i/o) pathway has been shown to be responsible for the well described triglyceride lowering effect of nicotinic acid in mice, while activation of the ß-arrestin pathway has been suggested to be responsible for its peripheral vasodilatory effect that causes cutaneous flushing. Several ligands have been described to selectively induce triglyceride lowering without inducing flushing. Cellular impedance has been demonstrated to determine G-protein coupled receptors activation in a G-protein specific manner. Agonists, which induce triglyceride lowering, but not flushing show a profile in cellular impedance that is distinct from the one induced by niacin and those compounds that induce triglyceride lowering as well as flushing. The strength of the signal correlates with the activation of ß-arrestin.
Subject(s)
Electric Impedance , Receptors, G-Protein-Coupled/agonists , Animals , Cell Line , Humans , Ligands , Mice , Niacin/pharmacology , Receptors, G-Protein-Coupled/analysis , Receptors, Nicotinic/analysis , Signal Transduction , Triglycerides/metabolismABSTRACT
Structure-guided lead optimization of recently described benzimidazolyl acetamides addressed the key liabilities of the previous lead compound 1. These efforts culminated in the discovery of 4-{(S)-2-[2-(4-chloro-phenyl)-5,6-difluoro-benzoimidazol-1-yl]-2-cyclohexyl-acetylamino}-3-fluoro-benzoic acid 7g, a highly potent and selective FXR agonist with excellent physicochemical and ADME properties and potent lipid lowering activity after oral administration to LDL receptor deficient mice.
Subject(s)
Benzimidazoles/chemistry , Receptors, Cytoplasmic and Nuclear/agonists , para-Aminobenzoates , 4-Aminobenzoic Acid/chemical synthesis , 4-Aminobenzoic Acid/chemistry , 4-Aminobenzoic Acid/pharmacokinetics , Administration, Oral , Animals , Benzimidazoles/chemical synthesis , Benzimidazoles/pharmacokinetics , Binding Sites , Computer Simulation , Crystallography, X-Ray , Humans , Male , Mice , Mice, Inbred C57BL , Microsomes, Liver/metabolism , Molecular Conformation , Rats , Rats, Wistar , Receptors, Cytoplasmic and Nuclear/metabolism , Receptors, LDL/deficiency , Receptors, LDL/genetics , Receptors, LDL/metabolism , Structure-Activity RelationshipABSTRACT
The development of new and broadly applicable linker groups which are stable under a variety of reaction conditions and allow release of the desired products from the solid support under very mild conditions is of great interest in organic synthesis and combinatorial chemistry. We describe an enzyme-labile safety-catch linker which releases alcohols and amines through i) enzymatic cleavage of an amino group and ii) subsequent lactam formation. The linker group was investigated on different polymeric supports: TentaGel. PEGA, CPG-beads and the soluble polymer POE-6000. From these linker-polymer conjugates 2-methoxy-5-nitrobenzyl alcohol was released by penicillin G acylase catalysed cleavage of a phenylacetamide and attack of the liberated benzylamine on the neighbouring ester group in ortho position. The model study revealed that only in the case of soluble POE-6000 conjugate high yields for the cleavage could be achieved. In the case of the other solid supports the enzyme does not have access to the interior of the polymer matrix. The application of the POE-6000 linker conjugate was investigated for various esters in Pd0-catalysed Heck-, Suzuki- and Sonogashira reactions as well as in a Mitsunobu reaction and cycloadditions. These studies proved that the linker is stable under a broad variety of reaction conditions and that the enzymatic method allows for release of the desired product alcohols under extremely mild conditions at pH 7 and 37 degrees C. In addition, the enzymatic reaction proceeds with complete chemoselectivity, that is other esters or amides are not attacked by the biocatalyst. In addition to alcohols amines can also be cleaved by means of the enzyme-initiated two-step process. In these cases the higher stability of amides as compared to esters requires warming to 60 degrees C to induce cyclization and release of the desired product.
ABSTRACT
Traceless release of biaryls, acetylenes, alkenes, heterocycles, thioethers, and secondary amines from different solid supports can be achieved under very mild conditions by using a hydrazide group. This group, which is converted into an acyl diazene by oxidation and subsequently cleaved by a nucleophile (see scheme), is thus an attractive new linker for solid-phase synthesis and combinatorial chemistry.
ABSTRACT
The effect of antiaggregating agents - acetylsalicyclic acid (ASA) and dipyridamol - on the rejection of allotransplanted canine kidneys in presensitized animals were studied. Blood flow dropped more markedly in the control group than in the group treated with ASA and dipyridamol. 24 hours after transplantation the blood flow in this group was significantly higher than in the control group (p 2,5 %) and in the third group treated with dipyridamol alone. The cellular rejection started earlier and was more pronounced in the control group. Only in this group vascular rejection and microthrombi were demonstrated. Urine output ceased 24 to 60 hours after transplantation. The immunosuppressive, antiphlogistic and platelet antiaggregating effect of the combined ASA and dipyridamol therapy is thought to be responsible for the better results in this group. In this experimental model the combined treatment of ASA and dipyridamol results in a later onset of cellular rejection, in better blood-flow of the kidney and later onset of anuria.
