4-(3-Aryloxyaryl)quinoline sulfones are potent liver X receptor agonists

A series of 4-(3-aryloxyaryl)quinolines with sulfone substituents on the terminal aryl ring (7) was prepared as LXR agonists. High affinity LXR ligands with excellent agonist potency and efficacy in functional assays of LXR activity were identified. In general, these sulfone agonists were equal to or superior to previously described alcohol and amide analogs in terms of affinity, functional potency, and microsomal stability. Many of the sulfones had LXRβ binding IC₅₀ values <10 nM while the most potent compounds in an ABCA1 mRNA induction assay in J774 mouse cells had EC₅₀ values <10 nM and were as efficacious as T0901317.     

1-(3-Aryloxyaryl)benzimidazole sulfones are liver X receptor agonists

A series of 1-(3-aryloxyaryl)benzimidazoles incorporating a sulfone substituent (6) was prepared. High affinity LXR ligands were identified (LXRβ binding IC₅₀ values <10 nM), some with excellent agonist potency and efficacy in a functional assay of LXR activity measuring ABCA1 mRNA increases in human macrophage THP1 cells. The compounds were typically stable in liver microsome preparations and had good oral exposure in mice.     

3-(3-Aryloxyaryl)imidazo[1,2-a]pyridine sulfones as liver X receptor agonists

Replacement of a quinoline with an imidazo[1,2-a]pyridine in a series of liver X receptor (LXR) agonists incorporating a [3-(sulfonyl)aryloxyphenyl] side chain provided high affinity LXR ligands 7. In functional assays of LXR activity, good agonist potency and efficacy were found for several analogs.     

Synthesis of 4-(3-biaryl)quinoline sulfones as potent liver X receptor agonists

A series of 4-(3-biaryl)quinolines with sulfone substituents on the terminal aryl ring (8) was prepared as potential LXR agonists. High affinity LXRβ ligands with generally modest binding selectivity over LXRα and excellent agonist potency in LXR functional assays were identified. Many compounds had LXRβ binding IC₅₀ values <10 nM while the most potent had EC₅₀ values <1.0 nM in an ABCA1 mRNA induction assay in J774 mouse cells with efficacy comparable to T0901317. Sulfone 8a was further evaluated in LDL (?/?) mice and shown to reduce atherosclerotic lesion progression.     

2-Aryl-N-acyl indole derivatives as liver X receptor (LXR) agonists

Structure-activity relationship studies on a series of Boc-indole derivatives as LXR agonists are described. Compound 1 was identified as an LXR agonist through structure-based virtual screening followed by high-throughput gene profiling. Replacement of the indan linker portion in 1 with an open-chain linker resulted in compounds with similar or improved in vitro potency and cellular functional activity. The Boc group at the N-1 position of the indole moiety can be replaced with a benzoyl group. The SAR studies led to the identification of compound 8, a potent LXRbeta agonist with an EC50 of 12 nM in the cofactor recruitment assay.     

Biarylether amide quinolines as liver X receptor agonists

A series of 4-(amido-biarylether)-quinolines was prepared as potential LXR agonists. Appropriate substitution with amide groups provided high affinity LXR ligands, some with excellent potency and efficacy in functional assays of LXR activity. Novel amide 4g had a binding IC₅₀ = 1.9 nM for LXRβ and EC₅₀ = 34 nM (96% efficacy relative to T0901317) in an ABCA1 gene expression assay in mouse J774 cells, demonstrating that 4-(biarylether)-quinolines with appropriate amide substitution are potent LXR agonists     

Pyrrolo(iso)quinoline derivatives as 5-HT(2C) receptor agonists

A series of 1-(1-pyrrolo(iso)quinolinyl)-2-propylamines was synthesised and evaluated as 5-HT(2C) receptor agonists for the treatment of obesity. The general methods of synthesis of the precursor indoles are described. The functional efficacy and radioligand binding data for the compounds at 5-HT(2) receptor subtypes are reported. The analogue which showed the highest 5-HT(2C) binding affinity (27, 1.6nM) was found to be successful in reducing food intake in rats.     

Hypolipidemic effects of selective liver X receptor alpha agonists

Recently, a number of nuclear receptors have been identified as key regulators of cholesterol homeostasis. Two of these, liver X receptor alpha (LXRalpha) (NR1H3) [1] and ubiquitous receptor (UR) (NR1H2) [1], appear to be involved in cholesterol reverse transport and disposal. LXRalpha null gene mice fail to adapt metabolically to high-cholesterol diets. We have recently shown that some 6alpha-hydroxylated bile acid analogs are selective activators of LXRalpha. In this report, we show that these orally administered LXRalpha agonists have an overall hypolipidemic effect in hypercholesterolemic rats, mice and hamsters, which indicates that in these animal models, endogenous LXRalpha agonist is a limiting factor for induction of cholesterol disposal. Furthermore, in animals, these 6alpha-hydroxylated bile acid analogs exhibit a unique pharmacokinetic profile and do not increase the serum triglyceride level; therefore, they may represent a novel class of therapeutic agents for cholesterol management.     

Discovery and structure-activity relationship studies of indole derivatives as liver X receptor (LXR) agonists

A structurally novel liver X receptor (LXR) agonist (1) was identified from internal compound collection utilizing the combination of structure-based virtual screening and high-throughput gene profiling. Compound 1 increased ABCA1 gene expression by eightfold and SREBP1c by threefold in differentiated THP-1 macrophage cell lines. Confirmation of its agonistic activity against LXR was obtained in the co-factor recruitment and reporter transactivation assays. Structure-activity relationship studies on compound 1 are described.     

Development of novel 2-[4-(aminoalkoxy)phenyl]-4(3H)-quinazolinone derivatives as potent and selective histamine H3 receptor inverse agonists

Novel 2-[4-(aminoalkoxy)phenyl]-4(3H)-quinazolinone derivatives were identified as potent human H(3) receptor inverse agonists. After systematic modification of lead 5a, the potent and selective analog 5r was identified. Elimination of hERG K(+) channel and human alpha(1A)-adrenoceptor activities is the main focus of the present study.     

2-Alkyl-3-(1,2,3,6-tetrahydropyridin-4-yl)-1H-indoles as novel 5-HT6 receptor agonists

A series of 2-alkyl-3-(1,2,3,6-tetrahydropyridin-4-yl)-1H-indoles were synthesized and evaluated for their 5-HT6 activity. The most potent agonist in this series was 5-chloro-2-methyl-3-(1,2,3,6-tetrahydropyridin-4-yl)-1H-indole with an IC50=7.4 nM in 3H-LSD binding and an EC50=1.0 nM in a functional assay measuring production of cyclic AMP.     

3-trifluoromethyl-4-nitro-5-arylpyrazoles are novel K(ATP) channel agonists

This communication describes the discovery and synthesis of a series of 3-trifluoromethyl-4-nitro-5-arylpyrazoles as potent K(ATP) channel agonists. The most potent compound reported is ca. 100-fold more potent than diazoxide and exhibits selectivity for the SUR1 K(ATP) channel subtype. The 4-nitro substitutent on the pyrazole ring was required for activity, and limited SAR suggests that the de-protonated pyrazole maybe the active species.     

3-Substituted 3-(4-aryloxyaryl)-propanoic acids as GPR40 agonists

The design, synthesis, and structure-activity relationship (SAR) for a series of β-substituted 3-(4-aryloxyaryl)propanoic acid GPR40 agonists is described. Systematic replacement of the pendant aryloxy group led to identification of potent GPR40 agonists. In order to identify candidates suitable for in vivo validation of the target, serum shifted potency and pharmacokinetic properties were determined for several compounds. Finally, further profiling of compound 7 is presented, including demonstration of enhanced glucose tolerance in an in vivo mouse model.     

Serotonin(4) (5-HT(4)) receptor agonists are putative antidepressants with a rapid onset of action

Current antidepressants are clinically effective only after several weeks of administration. Here, we show that serotonin(4) (5-HT(4)) agonists reduce immobility in the forced swimming test, displaying an antidepressant potential. Moreover, a 3 day regimen with such compounds modifies rat brain parameters considered to be key markers of antidepressant action, but that are observed only after 2-3 week treatments with classical molecules: desensitization of 5-HT(1A) autoreceptors, increased tonus on hippocampal postsynaptic 5-HT(1A) receptors, and enhanced phosphorylation of the CREB protein and neurogenesis in the hippocampus. In contrast, a 3 day treatment with the SSRI citalopram remains devoid of any effect on these parameters. Finally, a 3 day regimen with the 5-HT(4) agonist RS 67333 was sufficient to reduce both the hyperlocomotion induced by olfactory bulbectomy and the diminution of sucrose intake consecutive to a chronic mild stress. These findings point out 5-HT(4) receptor agonists as a putative class of antidepressants with a rapid onset of action.     

Synthesis and cytotoxic evaluation of certain 4-(phenylamino)furo[2,3-b]quinoline and 2-(furan-2-yl)-4-(phenylamino)quinoline derivatives

Certain 4-(phenylamino)furo[2,3-b]quinoline and 2-(furan-2-yl)-4-(phenylamino)quinoline derivatives were synthesized and evaluated in vitro against the full panel of NCIs 60 cancer cell lines. The preliminary results indicated these tricyclic 4-(phenylamino)furo[2,3-b]quinolines were more cytotoxic than their corresponding 2-(furan-2-yl)-4-(phenylamino)quinoline isomers. For the 4-(phenylamino)furo[2,3-b]quinolines, compounds 2a and 3d are two of the most potent with a mean GI50 value of 0.025 microM in each case. Inactivity of 2b and 2c (positional isomers of 2a) indicated that both electronic environment, and the distance between intercalating pharmacophore and H-bond-donating MeO group are important. For the 2-(furan-2-yl)-4-(phenylamino)quinoline isomers, compound 12 (a mean GI50 of 4.36 microM), which bears a para-COMe substituent, is more active than its meta-substituted counterpart 13 (10.5 microM). However, the electron-donating MeO substituent is preferred at the meta-position, and the cytotoxicity for the meta-substituted derivatives decreased in the order: MeO derivative 14b (3.05 microM) > oxime 16 (6.85 microM) > ketone 13 (10.5 microM) > methyl oxime 18 (20.6 microM).     

3-(Arylsulfonyl)-1-(azacyclyl)-1H-indoles are 5-HT6 receptor modulators

Novel 3-(arylsulfonyl)-1-(azacyclyl)-1H-indoles 6 were synthesized as potential 5-HT₆ receptor ligands, based on constraining a basic side chain as either a piperidine or a pyrrolidine. Many of these compounds had good 5-HT₆ binding affinity with K_i values <10 nM. Depending on substitution, both agonists (e.g., 6o: EC₅₀ = 60 nM, E_max = 70%) and antagonists (6y: IC₅₀ = 17 nM, I_max = 86%) were identified in a 5-HT₆ adenylyl cyclase assay.     

Design and synthesis of 4H-3-(2-phenoxy)phenyl-1,2,4-triazole derivatives as benzodiazepine receptor agonists

A series of new 5-substituted analogues of 4H-3-(2-phenoxy)phenyl-1,2,4-triazole and its chlorinated derivatives was designed and prepared. Conformational analysis and superimposition of energy minima conformers of the compounds on estazolam, a known benzodiazepine receptor agonist, revealed that the main proposed benzodiazepine pharmacophores were well matched. Rotarod and pentylenetetrazole-induced lethal convulsion tests showed that the introduction of an amino group in position 5 of 1,2,4-triazole ring especially in chlorinated derivatives had the best effect which was comparable with diazepam.     

Biocatalytic acylation of sugar alcohols by 3-(4-hydroxyphenyl)propionic acid

Enzymatic synthesis of aromatic esters of four different sugar alcohols (xylitol, arabitol, mannitol, and sorbitol) with 3-(4-hydroxyphenyl)propionic acid was performed in organic solvent medium, using immobilized Candida antarctica lipase (Novozyme 435), and molecular sieves for control of the water content. The influence of reaction parameters on the conversion has been investigated, including reaction time, temperature, alcohol/acid molar ratio, and enzyme amount. The highest conversions (94% for xylitol, 98% for arabitol, 80% for mannitol, and 93% for sorbitol) were obtained in pure tert-butanol at 60 °C and 72 h reaction time, 0.3 alcohol/acid molar ratio, and 0.5 g/mol enzyme/substrate ratio. The isolated new sugar alcohols esters were identified by different spectral analyses. MALDI-TOF MS analysis showed the formation of monoesters, diesters, and small quantities of triesters for all investigated sugar alcohols. The catalytic efficiency of the enzyme was higher for the pentitol substrates, decreasing in the following order: arabitol > xylitol > sorbitol > mannitol. These new compounds could have interesting applications in food, pharmaceutical and cosmetic formulations.