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.
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.
Nicotinic acid remains the most effective therapeutic agent for the treatment and prevention of atherosclerosis resulting from low high density lipoprotein cholesterol. The therapeutic actions of ...nicotinic acid are mediated by GPR109A, a Gi protein-coupled receptor, expressed primarily on adipocytes, Langerhans cells, and macrophage. Unfortunately, a severe, cutaneous flushing side effect limits its use and patient compliance. The mechanism of high density lipoprotein elevation is not clearly established but assumed to be influenced by an inhibition of lipolysis in the adipose. The flushing side effect appears to be mediated by the release of prostaglandin D2 from Langerhans cells in the skin. We hypothesized that the signal transduction pathways mediating the anti-lipolytic and prostaglandin D2/flushing pathways are distinct and that agonists may be identified that are capable of selectively eliciting the therapeutic, anti-lipolytic pathway while avoiding the activation of the parallel flush-inducing pathway. We have identified a number of GPR109A pyrazole agonists that are capable of fully inhibiting lipolysis in vitro and in vivo and not only fail to elicit a flushing response but can antagonize the ability of nicotinic acid to elicit a flush response in vivo. In contrast to flushing agonists, exposure of cells expressing GPR109A to the non-flushing agonists fails to induce internalization of the receptor or to activate ERK 1/2 mitogen-activated protein kinase phosphorylation.
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 5-N,N-difunctionalized 5-amino pyrazole-3-carboxylic acids and their agonist activity at GPR109b are reported.
A series of 5-N,N-disubstituted-5-aminopyrazole-3-carboxylic acids ...were prepared and found to act as highly potent and selective agonists of the G-Protein Coupled Receptor (GPCR) GPR109b, a low affinity receptor for niacin and some aromatic d-amino acids. Little activity was observed at the highly homologous higher affinity niacin receptor, GPR109a.
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.
We report the synthesis and structural characterization of modified Cram‐type, resorcin4arene‐based cavitands. Two main loci on the cavitand backbone were selected for structural modification: the ...upper part (wall domain) and the lower part (legs). Synthesis of unsymmetrically bridged cavitands with different wall components (i.e., 7, 8, and 14–18) was performed by stepwise bridging of the four couples of neighboring, H‐bonded OH‐groups of octol 1a (Schemes 1, 2, 4, and 5). Cavitands with modified legs (i.e., 20, 24, 27, and 28), targeted for surface immobilization, were synthesized by short routes starting from suitable aldehyde starting materials incorporating either the fully preformed leg moieties or functional precursors to the final legs (Schemes 7–10). The new cavitand substitution patterns described in this paper should enable the construction of a wide variety of functional architectures in the future. X‐Ray crystallography afforded the characterization of cavitands 2c (Fig. 3) and 24 (Fig. 7) in the vase conformation, with 2c featuring a well‐ordered CH2Cl2 guest molecule in its cavity. A particular highlight is the X‐ray crystal‐structure determination of octanitro derivative 19 (Scheme 6), which, for the first time, shows a cavitand, lacking substituents in the ortho‐position to the two O‐atoms of the four resorcinol moieties, in the kite‐conformation (Fig. 5).
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.
A selection of dimeric tetraethynylethenes (TEEs) and perethynylated expanded radialenes, containing different donor/acceptor substitution patterns, have been prepared and fully characterized. The ...first X‐ray crystal structure of an expanded 6radialene, with twelve peripheral 3,5‐di(tert‐butyl)phenyl substituents, is presented. This macrocycle, the all‐carbon core of which is isomeric with fullerene C60, adopts a non‐planar, “chair‐like” conformation. Also a TEE dimer, carrying N,N‐dimethylaniline donor substituents, has been subjected to an X‐ray crystallographic analysis. The electronic properties were studied by UV/Vis spectroscopy and electrochemistry, providing fundamental insight into mechanisms of π‐electron delocalization in the acyclic and macrocyclic chromophores. Donor or donor–acceptor‐substituted dimeric TEE derivatives show very strong absorptions extending over the entire UV/Vis region; their longest wavelength absorption bands have high charge‐transfer character. Macrocyclic cross‐conjugation in the expanded radialenes becomes increasingly efficient with increasing donor–acceptor polarization. A dual, strongly solvent‐polarity‐dependent fluorescence was observed for a tetrakis(N,N‐dimethylaniline)‐substituted dimeric TEE; this interesting emission behavior is explained by the twisted intramolecular charge‐transfer (TICT) state model. Donor‐substituted expanded radialenes display huge resonance‐enhanced third‐order nonlinear optical coefficients.
Expanded radialenes exhibit remarkable electronic properties owing to a considerable degree of macrocyclic cross‐conjugation. An expanded 6radialene (see figure, middle, m = 3) with a central C60 core adopts a chair‐like conformation as depicted according to an X‐ray analysis.
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