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.     

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.     

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

A series of 4-(3-aryloxyaryl)quinolines with alcohol substituents on the terminal aryl ring was prepared as potential LXR agonists, in which an alcohol group replaced an amide in previously reported amide analogs. High affinity LXR ligands with excellent agonist potency and efficacy in a functional model of LXR activity were identified, demonstrating that alcohols can substitute for amides while retaining LXR activity. The most potent compound was 5b which had an IC₅₀ = 3.3 nM for LXRβ binding and EC₅₀ = 12 nM (122% efficacy relative to T0901317) in an ABCA1 mRNA induction assay in J774 mouse cells.     

Discovery of novel potent GPR40 agonists containing imidazo[1,2-a]pyridine core as antidiabetic agents

Free fatty acid receptor 1 (FFA1 or GPR40) has been studied for many years as a target for the treatment of type 2 diabetes mellitus. In order to increase potency and reduce hepatotoxicity, a series of novel compounds containing imidazo[1,2-a]pyridine scaffold as GPR40 agonist were synthesized. Compound I-14 was identified as an effective agonist as shown by the conspicuous drop in blood glucose in normal and diabetic mice. It had no risk of hepatotoxicity compared with TAK-875. Moreover, good pharmacokinetic (PK) properties of I-14 were observed (CL = 27.26 ml/h/kg, t_1/2 = 5.93 h). The results indicate that I-14 could serve as a possible candidate to treat diabetes.     

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.     

Luminescence of imidazo[1,2-a]pyrazin-3(7H)-one compounds

In this review I will discuss chemical principles of the luminescence of imidazo[1,2-a]pyrazin-3(7H)-one compounds described to date. The review is composed of two main parts, the first dealing with the bioluminescence of coelenterate luciferin “coelenterazine” and Cypridina luciferin in marine organisms and the second with the chemiluminescence of these luciferins and their analogues. In the second section, possible applications of chemiluminescence and enhanced chemiluminescence in the area of bioassay are also discussed.     

Orally active C-6 heteroaryl- and heterocyclyl-substituted imidazo[1,2-a]pyridine acid pump antagonists (APAs)

Acid pump antagonists (APAs) such as the imidazo[1,2-a]pyridine AZD-0865 2 have proven efficacious at low oral doses in acid related gastric disorders. Herein we describe some of the broader SAR in this class of molecule and detail the discovery of an imidazo[1,2-a]pyridine 15 which has excellent efficacy in animal models of gastric acid secretion following oral administration, as well as a good overall developability profile. The discovery strategy focuses on use of heteroaryl and heterocyclic substituents at the C-6 position and optimization of developability characteristics through modulation of global physico-chemical properties.     

A novel series of imidazo[1,2-a]pyridine derivatives as HIF-1alpha prolyl hydroxylase inhibitors

Utilizing modeling information from a recently resolved structure of human HIF-1alpha prolyl hydroxylase (EGLN1) and structure-based design, a novel series of imidazo[1,2-a]pyridine derivatives was prepared. The activity of these compounds was determined in a human EGLN1 assay and a limited SAR was developed.     

Synthesis and biological evaluation of imidazo[1,2-a]pyridine derivatives as novel PI3 kinase p110alpha inhibitors

3-{1-[(4-Fluorophenyl)sulfonyl]-1H-pyrazol-3-yl}-2-methylimidazo[1,2-a]pyridine, 2a, was discovered in our chemical library as a novel p110alpha inhibitor with an IC(50) of 0.67microM, through screening in a scintillation proximity assay. Optimization of the substituents of 2a increased the p110alpha inhibitory activity by more than 300-fold (2g: IC(50)=0.0018microM). Further structural modification of 2g afforded thiazole derivative 12, which has potent p110alpha inhibitory activity (IC(50) of 0.0028microM) and is highly selective for p110alpha over other PI3K isoforms. Compound 12 also inhibited serum-induced cell proliferation of A375 and HeLa cells in vitro with IC(50) values of 0.14microM and 0.21microM, respectively, and suppressed tumor growth by 37% in a mouse HeLa xenograft model when dosed intraperitoneally at 25mg/kg. These results suggest that selective p110alpha inhibitors may have potential as cancer therapeutic agents.     

Research of imidazo[1,2-a]benzimidazole derivatives. XXX. Synthesis and properties of (imidazo[1,2-a]benzimidazolyl-2)acetic acid derivatives

Ethyl esters of (9-subtituted-imidazo[1,2-a]benzimidazolyl-2)acetic acids were synthesized. The chemical properties of these esters (hydrolysis, decarboxylation, hydrazinolysis) and biological activity (fungicidal, antimicrobial, antiarrhythmic activity, and also affects on the brain rhythmogenesis) of the prepared compounds were studied.     

2- and 3-substituted imidazo[1,2-a]pyrazines as inhibitors of bacterial type IV secretion

A novel series of 8-amino imidazo[1,2-a]pyrazine derivatives has been developed as inhibitors of the VirB11 ATPase HP0525, a key component of the bacterial type IV secretion system. A flexible synthetic route to both 2- and 3-aryl substituted regioisomers has been developed. The resulting series of imidazo[1,2-a]pyrazines has been used to probe the structure–activity relationships of these inhibitors, which show potential as antibacterial agents.     

Design and synthesis of acyclic nucleoside analogs with chlorinated imidazo[1,2-a]pyridine bases

A series of acyclic C-nucleoside analogs of 2,6-dichloro- and 2,6,7-trichloroimidazo[1,2-a]pyridine were synthesized and tested for antiviral activity. The appropriate hydroxymethyl-substituted heterocycles were treated successively with thionyl chloride, an appropriate nucleophile, then diisopropylethylamine to obtain the desired acyclic nucleoside analogs. These compounds were evaluated for activity against human cytomegalovirus and herpes simplex virus, type 1. Two of the dichloro analogs, but none of the trichloro analogs demonstrated slight antiviral activity (IC50's = 20-45 microM) at non-cytotoxic concentrations.     

Design,synthesis and biological evaluation of 2-(3,4-dimethoxyphenyl)-6 (1,2,3,6-tetrahydropyridin-4-yl)imidazo[1,2-a]pyridine analogues as antiproliferative agents

Two series of forty five novel 2-(3,4-dimethoxyphenyl)-6-(1,2,3,6-tetrahydropyridin-4-yl) imidazo[1,2-a]pyridine analogues (IPA 1–22, IPS 1–22 and IP-NH) have been designed, synthesized and structures confirmed by ¹H NMR, ¹³C NMR, mass spectrometry. Furthermore, single crystal was developed for IPS-13. All the final derived conjugates were evaluated for their in vitro antiproliferative activity against a panel of diverse cancer cell lines viz., A549 (lung cancer), HeLa (cervical cancer), B16F10 (melanoma) and found to show potent anticancer activity on the tested cell lines. Many of them showed the IC₅₀ values in the range 2.0–20.0 µM. The most active compounds (IPA 5,6,8,9,12,16,17,19 and IPS 7,8,9,22) from IPA and IPS series were screened to determine their cytotoxicity on HEK-293 (human embryonic kidney) normal cell line and were found to be nontoxic to normal human cells. The molecular interactions of the derivatised conjugates were also supported by molecular docking simulations. These derivatives may serve as lead structures for development of novel potential anticancer drug candidates.     

Structure-based design,synthesis, and evaluation of imidazo[1,2-b]pyridazine and imidazo[1,2-a]pyridine derivatives as novel dual c-Met and VEGFR2 kinase inhibitors

To identify compounds with potent antitumor efficacy for various human cancers, we aimed to synthesize compounds that could inhibit c-mesenchymal epithelial transition factor (c-Met) and vascular endothelial growth factor receptor 2 (VEGFR2) kinases. We designed para-substituted inhibitors by using co-crystal structural information from c-Met and VEGFR2 in complex with known inhibitors. This led to the identification of compounds 3a and 3b, which were capable of suppressing both c-Met and VEGFR2 kinase activities. Further optimization resulted in pyrazolone and pyridone derivatives, which could form intramolecular hydrogen bonds to enforce a rigid conformation, thereby producing potent inhibition. One compound of particular note was the imidazo[1,2-a]pyridine derivative (26) bearing a 6-methylpyridone ring, which strongly inhibited both c-Met and VEGFR2 enzyme activities (IC₅₀ = 1.9, 2.2 nM), as well as proliferation of c-Met-addicted MKN45 cells and VEGF-stimulated human umbilical vein endothelial cells (IC₅₀ = 5.0, 1.8 nM). Compound 26 exhibited dose-dependent antitumor efficacy in vivo in MKN45 (treated/control ratio [T/C] = 4%, po, 5 mg/kg, once-daily) and COLO205 (T/C = 13%, po, 15 mg/kg, once-daily) mouse xenograft models.     

8-Fluoroimidazo[1,2-a]pyridine: synthesis, physicochemical properties and evaluation as a bioisosteric replacement for imidazo[1,2-a]pyrimidine in an allosteric modulator ligand of the GABA A receptor

8-Fluoroimidazo[1,2-a]pyridine has been established as a physicochemical mimic of imidazo[1,2-a]pyrimidine, using both in silico and traditional techniques. Furthermore, a novel synthesis of a 3,7-disubstituted-8-fluoroimidazopyridine 3 has been developed and the utility of the physicochemical mimicry has been demonstrated in an in vitro system. Here, the 8-fluoroimidazopyridine ring contained in ligand 3 acts as a bioisosteric replacement for imidazopyrimidine in the GABA(A) receptor modulator 2.     

Synthesis and SAR of 2-(4-fluorophenyl)-3-pyrimidin-4-ylimidazo[1,2-a]pyridine derivatives as anticoccidial agents

Compounds 10a-10d and 10i are very potent inhibitors of Eimeria tenella cGMP-dependent protein kinase (0.081-0.32 nM) and are very efficacious antiparasitic agents in vivo when administered to chickens at 12.5-25 ppm levels in the feed.     

Synthesis and structure-activity relationship of imidazo[1,2-a]benzimidazoles as corticotropin-releasing factor 1 receptor antagonists

8-Aryl-1,3a,8-triaza-cyclopenta[a]indenes represent a novel series of high binding affinity corticotropin-releasing factor 1 receptor antagonists. Here, we report their synthesis, SAR, and pharmacokinetic properties of compound 8e (K(i) = 23 nM).     

Spiro(imidazo[1,2-a]pyrano[2,3-c]pyridine-9-indenes) as inhibitors of gastric acid secretion

Asymmetric and symmetric spiro(imidazo[1,2-a]pyrano[2,3-c]pyridine-9-indenes) were prepared using a synthetic approach that comprised a cross-metathesis reaction and an acid-catalyzed cycloisomerisation as key steps. The target compounds constitute potent inhibitors of the gastric proton pump enzyme with inhibitory activity comparable to potassium-competitive acid blockers (P-CABs) belonging to the known 9-aryl-7H-8,9-dihydropyrano[2,3-c]imidazo[1,2-a]pyridine series. Spiro(imidazo[1,2-a]pyrano[2,3-c]pyridine-9,2′-indenes) represent the first example for P-CABs, in which the distance between the heterocyclic scaffold and the aryl residue has been modified, and are promising candidates for further development as anti-ulcer drugs.     

In vitro and in vivo studies of 6,8-(diaryl)imidazo[1,2-a]pyrazin-3(7H)-ones as new antioxidants

A series of 5-aryl and 3,5-diaryl-2-amino-1,4-pyrazines and the derived imidazopyrazinones has been synthesized to study the chemical oxidative degradation of the bicyclic systems in vitro. Imidazopyrazinones mainly degraded following two independent pathways producing their precursors, namely aminopyrazines, and the corresponding amidopyrazines, respectively. Despite the fact that there is no influence of the substituent of the 3-aryl group on the ratio of the products aminopyrazine/amidopyrazine, diarylimidazopyrazinones and diarylaminopyrazines are good antioxidants in vivo. They protected against microvascular damages in ischemia/reperfusion with similar efficiencies.     

Discovery of imidazo[1,2-a]-, [1,2,4]triazolo[4,3-a]-, and [1,2,4]triazolo[1,5-a]pyridine-8-carboxamide negative allosteric modulators of metabotropic glutamate receptor subtype 5

Based on a hypothesis that an intramolecular hydrogen bond was present in our lead series of picolinamide mGlu₅ NAMs, we reasoned that an inactive nicotinamide series could be modified through introduction of a fused heterocyclic core to generate potent mGlu₅ NAMs. In this Letter, we describe the synthesis and evaluation of compounds that demonstrate the viability of that approach. Selected analogs were profiled in a variety of in vitro assays, and two compounds were evaluated in rat pharmacokinetic studies and a mouse model of obsessive-compulsive disorder. Ancillary pharmacology screening revealed that members of this series exhibited moderate inhibition of the dopamine transporter (DAT), and SAR was developed that expanded the selectivity for mGlu₅ versus DAT.