Bioisosteric approach to the discovery of imidazo[1,2-a]pyrazines as potent Aurora kinase inhibitors

Our continued effort toward the development of the imidazo[1,2-a]pyrazine scaffold as Aurora kinase inhibitors is described. Bioisosteric approach was applied to optimize the 8-position of the core. Several new potent Aurora A/B dual inhibitors, such as 25k and 25l, were identified.     

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.     

Imidazo[1,2-a]pyrazines as novel PI3K inhibitors

Phosphoinositide-3-kinase (PI3K) is an important target for cancer therapeutics due to the deregulation of its signaling pathway in a wide variety of human cancers. We describe herein a novel series of imidazo[1,2-a]pyrazines as PI3K inhibitors.     

Design and biological evaluation of imidazo[1,2-a]pyridines as novel and potent ASK1 inhibitors

Imidazo[1,2-a]pyridine derivatives were designed, synthesized, and evaluated as inhibitors of the apoptosis signal-regulating kinase 1 (ASK1). These were based on a benzothiazole derivative that was discovered from high-throughput screening of our compound library. As a result, we identified potent, selective, and orally bioavailable ASK1 inhibitors for wide range of therapeutic targets.     

Design and synthesis of novel imidazo[1,2-a]quinoxalines as PDE4 inhibitors

New imidazo[1,2-a]quinoxaline derivatives have been synthesised by condensation of an appropriate alpha-aminoalcohol with a quinoxaline followed by intramolecular cyclisation and nucleophilic substitutions. Their phosphodiesterase inhibitory activities have been assessed on a preparation of the PDE4 isoform purified from a human alveolar epithelial cell line (A549). These studies showed potent inhibitory properties that emphasize the importance of a methyl amino group at position 4 and a weakly hindered group at position 1.     

Synthesis and structure-activity relationship of imidazo(1,2-a)thieno(3,2-e)pyrazines as IKK-beta inhibitors

The identification of a potent series of IKK-beta selective inhibitors based on an imidazothienopyrazine template and the oral efficacy of one such analog (22j) in the LPS-induced TNF-alpha release mouse model are described.     

Synthesis and biological evaluation of benzo[4,5]imidazo[1,2-c]pyrimidine and benzo[4,5]imidazo[1,2-a]pyrazine derivatives as anaplastic lymphoma kinase inhibitors

Chromosomal translocations involving anaplastic lymphoma kinase (ALK) are the driving mutations for a range of cancers and ALK is thus considered an attractive therapeutic target. We synthesized a series of functionalized benzo[4,5]imidazo[1,2-c]pyrimidines and benzo[4,5]imidazo[1,2-a]pyrazines by an aza-Graebe–Ullman reaction, followed by palladium-catalyzed cross-coupling reactions. A sequential regioselective cross-coupling route is reported for the synthesis of unsymmetrically disubstituted benzo[4,5]imidazo[1,2-a]pyrazines. The inhibition of ALK was evaluated and compound 19 in particular showed good activity against both the wild type and crizotinib-resistant L1196M mutant in vitro and in ALK-transfected BaF3 cells.     

Synthesis and evaluation of imidazo[1,5-a]pyrazines as corticotropin releasing hormone receptor ligands

A novel series of imidazo[1,5-a]pyrazines was synthesized and evaluated as corticotropin releasing hormone (CRH) receptor ligands. SAR studies focused primarily on dialkylamino side chain optimization. SAR of the aryl and small alkyl substituents was also explored.     

Discovery of imidazo[1,2-a]pyrazine-based Aurora kinase inhibitors

The synthesis and structure–activity relationships (SAR) of novel, potent imidazo[1,2-a]pyrazine-based Aurora kinase inhibitors are described. The X-ray crystal structure of imidazo[1,2-a]pyrazine Aurora inhibitor 1j is disclosed. Compound 10i was identified as lead compound with a promising overall profile.     

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.     

Novel 2-phenylquinolin-7-yl-derived imidazo[1,5-a]pyrazines as potent insulin-like growth factor-I receptor (IGF-IR) inhibitors

A series of novel, potent quinolinyl-derived imidazo[1,5-a]pyrazine IGF-IR (IGF-1R) inhibitors--most notably, cis-3-(3-azetidin-1-ylmethylcyclobutyl)-1-(2-phenylquinolin-7-yl)imidazo[1,5-a]pyrazin-8-ylamine (AQIP)--is described. Synthetic details, structure-activity relationships, and in vitro biological activity are reported for the series. Key in vitro and in vivo biological results for AQIP are reported, including: inhibition of ligand-stimulated autophosphorylation of IGF-IR and downstream pathways in 3T3/huIGFIR cells; inhibition of proliferation and induction of DNA fragmentation in human tumor cell lines; a pharmacokinetic profile suitable for once-per-day oral dosing; antitumor activity in a 3T3/huIGFIR xenograft model; and effects on insulin and glucose levels.     

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.     

1,3-Disubstituted-imidazo[1,5-a]pyrazines as insulin-like growth-factor-I receptor (IGF-IR) inhibitors

A series of novel 8-amino-1,3-disubstituted-imidazo[1,5-a]pyrazines was designed and synthesized as IGF-IR inhibitors.     

Discovery of orally bioavailable imidazo[1,2-a]pyrazine-based Aurora kinase inhibitors

We report a series of potent imidazo[1,2-a]pyrazine-based Aurora kinase inhibitors. Optimization of the solvent accessible 8-position led to improvements in both oral bioavailability and off-target kinase inhibition. Compound 25 demonstrates anti-tumor activity in an A2780 ovarian tumor xenograft model.     

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.     

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.     

Synthesis and biological evaluation of sulfonylhydrazone-substituted imidazo[1,2-a]pyridines as novel PI3 kinase p110alpha inhibitors

We have previously reported the imidazo[1,2-a]pyridine derivative 4 as a novel p110alpha inhibitor; however, although 4 is a potent inhibitor of p110alpha enzymatic activity and tumor cell proliferation in vitro, it is unstable in solution and ineffective in vivo. To increase stability the pyrazole of 4 was replaced with a hydrazone and a moderately potent p110alpha inhibitor 7a was obtained. Subsequent optimization of 7a afforded exceptionally potent p110alpha inhibitors, including 8c and 8h, with IC(50) values of 0.30 nM and 0.26 nM, respectively; to the best of our knowledge, these compounds are the most potent PI3K p110alpha inhibitors reported to date. Compound 8c was also stable in solution and exhibited significant anti-tumor effectiveness in vivo.     

Discovery of novel imidazo[1,2-a]pyrazin-8-amines as Brk/PTK6 inhibitors

A series of substituted imidazo[1,2-a]pyrazin-8-amines were discovered as novel breast tumor kinase (Brk)/protein tyrosine kinase 6 (PTK6) inhibitors. Tool compounds with low-nanomolar Brk inhibition activity, high selectivity towards other kinases and desirable DMPK properties were achieved to enable the exploration of Brk as an oncology target.     

Potency switch between CHK1 and MK2: Discovery of imidazo[1,2-a]pyrazine- and imidazo[1,2-c]pyrimidine-based kinase inhibitors

Chemistry has been developed to access both imidazo[1,2-a]pyrazines and imidazo[1,2-c]pyrimidines. Small structural modifications in both series led to a switch of potency between two kinases involved in mediating cell cycle checkpoint control, CHK1 and MK2.