1-Substituted benzotriazole carboxylic acids have been identified as the first reported examples of selective small-molecule agonists of the human orphan G-protein-coupled receptor GPR109b (HM74), a ...low-affinity receptor for the HDL-raising drug niacin. No activity was observed at the highly homologous high-affinity niacin receptor GPR109a (HM74A). The high degree of selectivity was attributed to a difference in the amino acid sequence adjacent to a key arginine−ligand interaction allowing somewhat larger ligands to be tolerated by GPR109b.
The discovery and profiling of 3-(1H-tetrazol-5-yl)-1,4,5,6-tetrahydro-cyclopentapyrazole (5a, MK-0354), a partial agonist of GPR109a, is described. Compound 5a retained the plasma free fatty acid ...lowering effects in mice associated with GPR109a agonism, but did not induce vasodilation at the maximum feasible dose. Moreover, preadministration of 5a blocked the flushing effect induced by nicotinic acid but not that induced by PGD2. This profile made 5a a suitable candidate for further study for the treatment of dyslipidemia.
G-protein coupled receptor (GPCR) GPR109a is a molecular target for nicotinic acid and is expressed in adipocytes, spleen, and immune cells. Nicotinic acid has long been used for the treatment of ...dyslipidemia due to its capacity to positively affect serum lipids to a greater extent than other currently marketed drugs. We report a series of tricyclic pyrazole carboxylic acids that are potent and selective agonists of GPR109a. Compound R,R-19a (MK-1903) was advanced through preclinical studies, was well tolerated, and presented no apparent safety concerns. Compound R,R-19a was advanced into a phase 1 clinical trial and produced a robust decrease in plasma free fatty acids. On the basis of these results, R,R-19a was evaluated in a phase 2 study in humans. Because R,R-19a produced only a weak effect on serum lipids as compared with niacin, we conclude that the beneficial effects of niacin are most likely the result of an undefined GPR109a independent pathway.
A series of 4-fluoro-5-functionalized pyrazole-3 carboxylic acids were shown to be potent, selective agonists of GPR109a. Improved free fatty acid reduction was observed when compared to niacin.
A ...series of 5-alkyl pyrazole-3-carboxylic acids were prepared and found to act as potent and selective agonists of the human GPCR, GPR109a, the high affinity nicotinic acid receptor. No activity was observed at the highly homologous low affinity niacin receptor, GPR109b. A further series of 4-fluoro-5-alkyl pyrazole-3-carboxylic acids were shown to display similar potency. One example from the series was shown to have improved properties in vivo compared to niacin.
Tricyclic pyrazole tetrazoles which are potent partial agonists of the high affinity niacin receptor, GPR109a, have been discovered and optimized. One of these compounds has proven to be effective at ...lowering free fatty acids in vitro and in vivo.
Tricyclic pyrazole tetrazoles which are potent partial agonists of the high affinity niacin receptor, GPR109a, have been discovered and optimized. One of these compounds has proven to be effective at lowering free fatty acids in vitro and in vivo.
A series of novel functionalized 3-nitro-4-amino benzoic acids and 6-amino nicotinic acids and their agonist activity at GPR109b are reported.
A series of 3-nitro-4-substituted-aminobenzoic acids ...were prepared and found to act as potent and highly selective agonists of the orphan human GPCR GPR109b, a low affinity receptor for niacin. No activity was observed at the closely homologous high affinity niacin receptor, GPR109a. A second series, comprising 6-amino-substituted nicotinic acids was, also prepared and several analogues showed comparable activity to the nitroaryl series.
A strategy for lead identification of new agonists of GPR109a is described. Early compound triage led us to focus on a series of pyrazole acid derivatives. Further elaboration of these compounds ...provided a series of 5,5-fused pyrazoles to be used as lead compounds for further optimization.
A strategy for lead identification of new agonists of GPR109a, starting from known compounds shown to activate the receptor, is described. Early compound triage led to the formulation of a binding hypothesis and eventually to our focus on a series of pyrazole acid derivatives. Further elaboration of these compounds provided a series of 5,5-fused pyrazoles to be used as lead compounds for further optimization.
Metalloproteins are involved in key cell processes such as photosynthesis, respiration, and oxygen transport. However, the presence of transition metals (notably iron as a component of Fe-S clusters) ...often makes these proteins sensitive to oxygen-induced degradation. Consequently, their study usually requires strict anaerobic conditions. Although X-ray crystallography has been the method of choice for solving macromolecular structures for many years, recently electron microscopy has also become an increasingly powerful structure-solving technique. We have used our previous experience with cryo-crystallography to develop a method to prepare cryo-EM grids in an anaerobic chamber and have applied it to solve the structures of apoferritin and the 3 Fe
S
-containing pyruvate ferredoxin oxidoreductase (PFOR) at 2.40 Å and 2.90 Å resolution, respectively. The maps are of similar quality to the ones obtained under air, thereby validating our method as an improvement in the structural investigation of oxygen-sensitive metalloproteins by cryo-EM.
Magnitudes of terrestrial (fresh) and marine (saline) sources of submarine groundwater discharge (SGD) are estimated for a transect across Indian River Lagoon, Florida. Two independent techniques ...(seepage meters and pore water Cl- concentrations) show terrestrial SGD decreases linearly to around 22 m offshore, and these techniques, together with a model based on the width of the outflow face, indicate a cumulative discharge of between 0.02 and 0.9 m3/d per meter of shoreline. Seepage meters and models of the deficiencies in (222)Rn activity in shallow sediments indicate marine SGD discharges of roughly 117 m3/d per meter of shoreline across the entire 1800-m-wide transect. Two surface streams nearest the transect have an average discharge of about 28 m3/d per meter of shoreline. Marine SGD is thus 4 times greater then surface water discharge and more than 2 orders of magnitude greater than terrestrial SGD. The magnitude of the terrestrial SGD is limited by the amount of regional precipitation, evaporation, recharge, and groundwater usage, while marine SGD is limited only by processes circulating marine water into and out of the sediments. The large magnitude of marine SGD means that it could be important for estuarine cycling of reactive components such as nutrients and metals with only slight modification from estuarine water compositions. The small magnitude of terrestrial SGD means that large differences from estuarine water composition would be required to affect chemical cycling.
