Discovery of novel tricyclic pyrido[3′,2′:4,5]thieno[3,2-d]pyrimidin-4-amine derivatives as VEGFR-2 inhibitors

In an effort to develop ATP-competitive VEGFR-2 selective inhibitors, a novel series of tricyclic pyrido[3′,2′:4,5]thieno[3,2-d]pyrimidin-4-amine derivatives were designed and synthesized. These compounds were characterized by IR, ¹H NMR, ¹³C NMR, elemental and mass spectral analyses. Docking studies have given a partial insight into the molecular determinants of the activity of this novel series in VEGFR-2 kinase active site. Moreover, these compounds were assessed at 10 μM for their selective inhibitory activities over a panel of 6 human kinases, namely VEGFR-1/Flt-1, VEGFR-2/KDR, EGFR, CDK5/p25, GSK3α and GSK3β. Compound N-(4,6-dimethylthieno[2,3-b]pyridine)-7,9-dimethylpyrido[3′,2′:4,5]thieno[3,2-d]pyrimidin-4-amine (9d) exhibited the most potent and selective inhibitory activity against VEGFR-2/KDR over the six human kinases, with an IC₅₀ value 2.6 μM. The identification of this hit candidate could aid the design of new tricyclic-based VEGFR-2 kinase modulators.     

A new therapeutic approach in Parkinson’s disease: Some novel quinazoline derivatives as dual selective phosphodiesterase 1 inhibitors and anti-inflammatory agents

The increasing life expectancy in our population makes Parkinson’s disease (PD) a growing public health problem. There is a great need to find a way to prevent and delay the disease. It was shown that selective phosphodiesterase 1 (PDE1) inhibitors and anti-inflammatory agents might be effective in treating PD. Therefore, a novel 1,2,9,11-tetrasubstituted-7H-thieno[2′,3′:4,5]pyrimido[6,1-b]-quinazolin-7-one (1–15) and 1,3,10,12-tetrasubstituted-8H-pyrido[2′,3′:4,5]pyrimido[6,1-b]quinazolin-8-one (16–36) derivatives were synthesized by reported method and investigated for their ability to inhibit PDE1. Most of the synthesized compounds have shown good activity against PDE1 and were less effective than 3-isobutyl-1-methylxanthine. All the compounds were also tested for their in vitro anti-inflammatory activity by carrageenan-induced oedema in rats. In addition, ulcerogenic activity was determined. The combined anti-inflammatory data from in vitro animal model showed that compounds, 9,11-dibromo-1-(2-furyl)-3-(4-tolyl)-8H-pyrido[2′,3′:4,5]pyrimido[6,1-b]quinazolin-8-one 23, 9,11-dibromo-1-(4-methoxy-phenyl)-3-phenyl-8H-pyrido[2′,3′:4,5]pyrimido[6,1-b]quinazolin-8-one 24, 9,11-dibromo-1-(4-chloro-phenyl)-3-(4-tolyl)-8H-pyrido[2′,3′:4,5]pyrimido[6,1-b]quinazolin-8-one 29 and 9-bromo-1-(4-chloro-phenyl)-3-(4-tolyl)-8H-pyrido[2′,3′:4,5]pyrimido[6,1-b]quinazolin-8-one 36 exhibited even more potent anti-inflammatory activity and low gastric ulceration incidence compare to reference standard Indomethacin. Since compound 23, 24, 29 and 36 exhibits both anti-inflammatory activity and PDE1 inhibition, it needs further detailed studies.     

Design,synthesis, and structure–activity relationships of pyrimido[4,5-b]indole-4-amines as microtubule depolymerizing agents that are effective against multidrug resistant cells

To identify the structural features of 9H-pyrimido[4,5-b]indoles as microtubule depolymerizers, pyrimido[4,5-b]indoles 2–8 with varied substituents at the 2-, 4- and 5-positions were designed and synthesized. Nucleophilic displacement of 2,5-substituted-4-chloro-pyrimido[4,5-b]indoles with appropriate arylamines was the final step employed in the synthesis of target compounds 2–8. Compounds 2 and 6 had two-digit nanomolar potency (IC₅₀) against MDA-MB-435, SK-OV-3 and HeLa cancer cells in vitro. Compounds 2 and 6 also depolymerized microtubules comparable to the lead compound 1. Compounds 2, 3, 6 and 8 were effective in cells expressing P-glycoprotein or the βIII isotype of tubulin, mechanisms that are associated with clinical drug resistance to microtubule targeting drugs. Proton NMR and molecular modeling studies were employed to identify the structural basis for the microtubule depolymerizing activity of pyrimido[4,5-b]indoles.     

Novel pyrimidine-pyridine hybrids: Synthesis,cyclooxygenase inhibition,anti-inflammatory activity and ulcerogenic liability

Some derivatives containing pyrido[2,3-d:6,5d′]dipyrimidine-4,5-diones (9a-f), tetrahydropyrido[2,3-d]pyrimidine-6-carbonitriles (11a-c) and 6-(4-acetylphenyl)-2-thioxo-2,3,5,6,7,8-hexahydro-1H-pyrimido[4,5-d]pyrimidin-4-one (12) were synthesized from 6-amino-2-thioxo-2,3-dihydro-1H-pyrimidin-4-one (8). The anti-inflammatory effect of these candidates was determined and the ulcer indices were calculated for active compounds. 7-Amino-5-(3,4,5-trimethoxyphenyl)-4-oxo-2-thioxo-1,2,3,4-tetrahydropyrido[2,3-d] pyrimidine-6-carbonitrile (11c) exhibited better edema inhibition than celecoxib. Moreover, compounds 9b, 9d and 11c revealed better COX-2 inhibitory activity in a range (IC₅₀ = 0.25–0.89 µM) than celecoxib (IC₅₀ = 1.11 µM). Regarding ulcerogenic liability, all of the compounds under the study were less ulcerogenic than indomethacin. Molecular docking studies had been carried on active candidates 9d and 11c to explore action mode of these candidates as leads for discovering other anti-inflammatory agents.     

Fluorescent cytokinins: Stretched-out analogs of N6-benzyladenine and N6-(Δ2-isopentenyl) adenine

We have synthesized and compared the cytokinin activities in the tobacco bioassay of a series of benzologs of 6-(3-methyl-2-butenylamino)purine (N⁶-(Δ²-isopentenyl)adenine) (1a) and 6-benzylaminopurine (N⁶-benzyl-adenine) (1c). The linear benzo analogs 8-(3-methyl-2-butenylamino)imidazo[4,5-g]quinazoline (2b) and 8-benzyla-minoimidazo[4,5-g]quinazoline (2c) are active, while 9-(3-methyl-2-butenylamino)imidazo[4,5-f]quinazoline (3b) and 6-(3-methyl-2-butenylamino)imidazo[4,5-h]quinazoline (4b) are slightly active and 9-benzylaminoimidazo[4,5-f]-quinazoline (3c) and 6-benzylaminoimidazo[4,5-h]quinazoline (4c) are inactive. Compounds 2b and 2c represent the first examples of active cytokinins containing a tri-heterocyclic moiety. The above series of compounds demonstrates structural factors that affect cytokinin activity. These compounds also have interesting fluorescence properties which could render them useful as probes to study the mechanism of cytokinin action.     

Design,synthesis and biological evaluation of novel 3H-imidazole [4,5-b] pyridine derivatives as selective mTOR inhibitors

A series of 3H-imidazo [4,5-b] pyridines derivatives were designed and synthesized as selective mTOR inhibitors. The systematic optimization of the molecules resulted in the identification of two compounds 10d and 10n with nanomolar mTOR inhibitory activity and selectivity over PI3Kα. Besides, compounds 10d and 10n demonstrated attractive potency against human breast cancer cells (MCF-7) and human ovarian cancer cell (A2780).     

Synthesis and biological activity of N4-phenylsubstituted-6-(2,4-dichloro phenylmethyl)-7H-pyrrolo[2,3-d]pyrimidine-2,4-diamines as vascular endothelial growth factor receptor-2 inhibitors and antiangiogenic and antitumor agents

A series of eight N⁴-phenylsubstituted-6-(2,4-dichlorophenylmethyl)-7H-pyrrolo[2,3-d]pyrimidine-2,4-diamines 8–15 were synthesized as vascular endothelial growth factor receptor-2 (VEGFR-2) inhibitors with varied substitutions in the phenyl ring of the 4-anilino moiety. In addition, five N⁴-phenylsubstituted-6-phenylmethylsubstituted-7H-pyrrolo[2,3-d]pyrimidin-4-amines 16–20 were synthesized to evaluate the importance of the 2-NH₂ moiety for multiple receptor tyrosine kinase (RTK) inhibition. Cyclocondensation of α-halomethylbenzylketones with 2,6-diamino-4-hydroxypyrimidine afforded 2-amino-6-(2,4-dichlorophenylmethyl)-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one, 23 and reaction of α-bromomethylbenzylketones with ethylamidinoacetate followed by cyclocondensation with formamide afforded the 6-phenylmethylsubstituted-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-ones, 40–42, respectively. Chlorination of the 4-position and displacement with appropriate anilines afforded the target compounds 8–20. Compounds 8, 10 and 14 were potent VEGFR-2 inhibitors and were 100-fold, 40-fold and 8-fold more potent than the standard semaxanib, respectively. Previously synthesized multiple RTK inhibitor, 5 and the VEGFR-2 inhibitor 8 from this study, were chosen for further evaluation in a mouse orthotopic model of melanoma and showed significant inhibition of tumor growth, angiogenesis and metastasis.     

Facile synthesis of SSR180575 and discovery of 7-chloro-N,N,5-trimethyl-4-oxo-3(6-[18F]fluoropyridin-2-yl)-3,5-dihydro-4H-pyridazino[4,5-b]indole-1-acetamide,a potent pyridazinoindole ligand for PET imaging of TSPO in cancer

A novel synthesis of the translocator protein (TSPO) ligand 7-chloro-N,N,5-trimethyl-4-oxo-3-phenyl-3,5-dihydro-4H-pyridazino[4,5-b]indole-1-acetamide (SSR180575, 3) was achieved in four steps from commercially available starting materials. Focused structure–activity relationship development about the pyridazinoindole ring at the N3 position led to the discovery of 7-chloro-N,N,5-trimethyl-4-oxo-3(6-fluoropyridin-2-yl)-3,5-dihydro-4H-pyridazino[4,5-b]indole-1-acetamide (14), a novel ligand of comparable affinity. Radiolabeling with fluorine-18 (¹⁸F) yielded 7-chloro-N,N,5-trimethyl-4-oxo-3(6-[¹⁸F]fluoropyridin-2-yl)-3,5-dihydro-4H-pyridazino[4,5-b]indole-1-acetamide ([¹⁸F]-14) in high radiochemical yield and specific activity. In vivo studies of [¹⁸F]-14 revealed this agent as a promising probe for molecular imaging of glioma.     

Synthesis of N4-(substituted phenyl)-N4-alkyl/desalkyl-9H-pyrimido[4,5-b]indole-2,4-diamines and identification of new microtubule disrupting compounds that are effective against multidrug resistant cells

A series of fourteen N⁴-(substituted phenyl)-N⁴-alkyl/desalkyl-9H-pyrimido[4,5-b]indole-2,4-diamines was synthesized as potential microtubule targeting agents. The synthesis involved a Fisher indole cyclization of 2-amino-6-hydrazinylpyrimidin-4(3H)-one with cyclohexanone, followed by oxidation, chlorination and displacement with appropriate anilines. Compounds 6, 14 and 15 had low nanomolar potency against MDA-MB-435 tumor cells and depolymerized microtubules. Compound 6 additionally had nanomolar GI₅₀ values against 57 of the NCI 60-tumor panel cell lines. Mechanistic studies showed that 6 inhibited tubulin polymerization and [³H]colchicine binding to tubulin. The most potent compounds were all effective in cells expressing P-glycoprotein or the βIII isotype of tubulin, which have been associated with clinical drug resistance. Modeling studies provided the potential interactions of 6, 14 and 15 within the colchicine site.     

Synthesis and anti-tumor activity of [1,4] dioxino [2,3-f] quinazoline derivatives as dual inhibitors of c-Met and VEGFR-2

Both c-Met and VEGFR-2 were important targets for cancer therapies. In order to develop reversible and non-covalent c-Met and VEGFR-2 dual inhibitors, a series of [1,4]dioxino[2,3-f]quinazoline derivatives were designed and synthesized. The enzyme assay demonstrated that most target compounds had inhibition potency on both c-Met and VEGFR-2 with IC₅₀ values in nanomolar range especially compounds 7m and 7k. Based on further cell proliferation assay in vitro, compound 7k showed significantly anti-tumor activity in vivo on a hepatocellular carcinoma (MHCC97H cells) xenograft mouse model. We docked the compound 7m with c-Met and VEGFR-2 kinases, and interpreted the SAR of these analogues. All results indicated that the target compounds were dual inhibitors of c-Met and VEGFR-2 kinases that held promising potential in cancer therapy.     

Synthesis of carbon-11-labeled CK1 inhibitors as new potential PET radiotracers for imaging of Alzheimer’s disease

The reference standards methyl 3-((2,2-difluoro-5H-[1,3]dioxolo[4′,5′:4,5]benzo[1,2-d]imidazol-6-yl)carbamoyl)benzoate (5a) and N-(2,2-difluoro-5H-[1,3]dioxolo[4′,5′:4,5]benzo[1,2-d]imidazol-6-yl)-3-methoxybenzamide (5c), and their corresponding desmethylated precursors 3-((2,2-difluoro-5H-[1,3]dioxolo[4′,5′:4,5]benzo[1,2-d]imidazol-6-yl)carbamoyl)benzoic acid (6a) and N-(2,2-difluoro-5H-[1,3]dioxolo[4′,5′:4,5]benzo[1,2-d]imidazol-6-yl)-3-hydroxybenzamide (6b), were synthesized from 5-amino-2,2-difluoro-1,3-benzodioxole and 3-substituted benzoic acids in 5 and 6 steps with 33% and 11%, 30% and 7% overall chemical yield, respectively. Carbon-11-labeled casein kinase 1 (CK1) inhibitors, [¹¹C]methyl 3-((2,2-difluoro-5H-[1,3]dioxolo[4′,5′:4,5]benzo[1,2-d]imidazol-6-yl)carbamoyl)benzoate ([¹¹C]5a) and N-(2,2-difluoro-5H-[1,3]dioxolo[4′,5′:4,5]benzo[1,2-d]imidazol-6-yl)-3-[¹¹C]methoxybenzamide ([¹¹C]5c), were prepared from their O-desmethylated precursor 6a or 6b with [¹¹C]CH₃OTf through O-[¹¹C]methylation and isolated by HPLC combined with SPE in 40–45% radiochemical yield, based on [¹¹C]CO₂ and decay corrected to end of bombardment (EOB). The radiochemical purity was >99%, and the molar activity (MA) at EOB was 370–740?GBq/μmol with a total synthesis time of ～40-min from EOB.     

Imidazo[2′,1′:2,3]thiazolo[4,5-d]pyridazinone as a new scaffold of DHFR inhibitors: Synthesis,biological evaluation and molecular modeling study

New series of thiazolo[4,5-d]pyridazin and imidazo[2′,1′:2,3]thiazolo[4,5-d]pyridazin analogues were designed, synthesized and evaluated for their in vitro DHFR inhibition and antitumor activity. Compounds 13 and 43 proved to be DHFR inhibitors with IC₅₀ 0.05 and 0.06 μM, respectively. 43 proved lethal to OVCAR-3 Ovarian cancer and MDA-MB-435 Melanoma at IC₅₀ 0.32 and 0.46 μM, respectively. The active compounds formed hydrogen bond at DHFR binding site between N₁-nitrogen of the pyridazine ring with Glu30; the carbonyl group with Trp24, Arg70 or Lys64; π-cation interaction with Arg22 and π-π interaction with Phe31 residues. Ring annexation of the active 1,3-thiazole ring analogue 13 into the bicyclic thiazolo[4,5-d]pyridazine (18,19) or imidazo[2,1-b]thiazoles (23–25) decreased the DHFR inhibition activity; while the formation of the tricyclic imidazo[2′,1′:2,3]-thiazolo[4,5-d]pyridazine (43–54) increased potency. The obtained model could be useful for the development of new class of DHFR inhibitors.     

Identification of new pyrrolo[2,3-d]pyrimidines as potent VEGFR-2 tyrosine kinase inhibitors: Design,synthesis, biological evaluation and molecular modeling

Vascular endothelial growth factor receptor-2 (VEGFR-2) plays a crucial role in cancer angiogenesis. In the current study, a series of novel pyrrolo[2,3-d]pyrimidine based-compounds was designed and synthesized as VEGFR-2 inhibitors, in accordance to the structure activity relationship (SAR) studies of known type II VEGFR-2 inhibitors. The newly synthesized compounds were evaluated for their ability to inhibit VEGFR-2 kinase enzyme in vitro. All the tested compounds demonstrated highly potent dose-related VEGFR-2 inhibition with IC₅₀ values in nanomolar range. Among these compounds, pyrrolo[2,3-d]pyrimidine derivatives carrying biaryl urea moieties (12d and 15c) exhibited IC₅₀ values of 11.9 and 13.6 nM respectively. Additionally, most of the newly synthesized final compounds were tested on 60 human cancer cell lines. Docking of these compounds into the inactive conformation of VEGFR-2 was performed which showed comparable binding modes to that of the FDA approved VEGFR-2 kinase inhibitors. These newly discovered potent kinase inhibitors could be considered as potential candidates for the development of new targeted anticancer agent.     

Phosphodiesterase inhibitors. Part 6: Design,synthesis, and structure–activity relationships of PDE4-inhibitory pyrazolo[1,5-a]pyridines with anti-inflammatory activity

We previously identified KCA-1490 [(?)-6-(7-methoxy-2-trifluoromethyl-pyrazolo[1,5-a]pyridin-4-yl)-5-methyl-4,5-dihydro-3-(2H)-pyridazinone], a dual PDE3/4 inhibitor. In the present study, we found highly potent selective PDE4 inhibitors derived from the structure of KCA-1490. Among them, N-(3,5-dichloropyridin-4-yl)-7-methoxy-2-(trifluoromethyl)pyrazolo[1,5-a]pyridine-4-carboxamide (2a) had good anti-inflammatory effects in an animal model.     

Synthesis and cytokinin activity of N-acylaminodeazapurines

Three 7-acylaminoimidazo[4,5-b]pyridines, namely 7-pentanoylaminoimidazo[4,5-b]pyridine (1), 7-benzoylaminoimidazo[4,5-b]pyridine(2), and 7-(2-furoylamino)imidazo[4,5-b]pyridine(3), six 4-acylaminoimidazo[4,5-c]pyridines, namely 4-propionylaminoimidazo[4,5-c]pyridine(4), 4-butyryl-aminoimidazo[4,5-c]pyridine(5), 4-pentanoylaminoimidazo[4,5-c]pyridine(6) 4-hexanoylaminoimidazo[4,5-c]pyridine(7),4-benzoylaminoimidazo[4,5-c]pyridine(8), and 4-(2-furoylamino)imidazo[4,5-c]-pyridine(9), and seven 7-acylaminoimidazo[4,5-c]pyridines, namely 7-propionylaminoimidazo[4,5-c]-pyridine(10), 7-butyrylaminoimidazo[4,5-c]pyridine(11), 7-pentanoylaminoimidazo[4,5-c]pyridine(12), 7-hexanoylaminoimidazo[4,5-c]pyridine(13), 7-benzoylaminoimidazo[4,5-c]pyridine(14), 7-phenylacetylaminoimidazo[4,5-c]pyridine(15), and 7-(2-furoylamino)imidazo[4,5-c]pyridine(16) were synthesized and tested for their cytokinin activity with the tobacco callus bioassay. 2 showed a cytokinin activity at 1 × 10⁻⁸ M and gave a callus yield about 72% of that produced by kinetin at 1 × 10⁻⁶ M. 1, 3 and 8 showed the optimum growth responses in the range of 10⁻⁷−10⁻⁶ M. 4, 5, 7, 9–16 were slightly active. These results support previous reports that a nitrogen atom at the 3-position in the purine ring plays an important role in conferring high cytokinin activity.     

Synthesis of novel hetero ring fused pyridine derivatives; Their anticancer activity,CoMFA and CoMSIA studies

A series of novel furo[2,3-b]pyridine-2-carboxamide 4a–h/pyrido[3′,2′:4,5]furo[3,2-d] pyrimidin-4(3H)-one derivatives 5a–p were prepared from pyridin 2(1H) one 1 via selective O-alkylation with α-bromoethylester followed by cyclization, then reaction with different aliphatic primary amines to obtain 4 and further reaction with triethyl orthoacetate/triethyl orthoformate. Also prepared novel furo[2,3-b]pyridine-2-carbohydrazide Schiff’s bases 7a–h and pyrido [3′,2′:4,5]furo[3,2-d]pyrimidin-4(3H)-one derivatives 8a–h starting from furo[2,3-b]pyridine carboxylate derivatives 3 by reaction with hydrazine hydrate to form 6 and reaction with diverse substituted aldehydes and cyclization. Products 4a–h, 5a–p, 7a–h and 8a–h were screened against four human cancer cell lines (HeLa, COLO205, Hep G2 and MCF 7) and one normal cell line (HEK 293). Compounds 4e, 4f, 4g, 5h, 7c, 7d, 7e and 7f showed significant anticancer activity against all the cell lines at micro molar concentration and found to be non-toxic to normal cell line. Studies for HeLa, COLO205 and MCF-7 using CoMFA and CoMSIA. Models from 3D-QSAR provided a strong basis for future rational design of more active and selective HeLa, COLO205 and MCF-7 cell line inhibitors.     

Synthesis,cytotoxicity, antimicrobial and anti-biofilm activities of novel pyrazolo[3,4-b]pyridine and pyrimidine functionalized 1,2,3-triazole derivatives

A series of novel pyrazolo[3,4-b]pyridine and pyrimidine functionalized 1,2,3-triazole derivatives 8a–g and 9a–g were prepared starting from 6-trifluoromethylpyridine-2(1H)one 2 via selective O-alkylation, followed by cyclisation using hydrazine hydrate to obtain 6-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyridin-3-amine 4. Compound 4 was diazotized followed by reaction with sodium azide, resulted in 3-azido-6-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyridine 5. Compound 5 was further cyclized with N-/O-propargylated pyrimidine derivatives under Sharpless conditions and obtained compounds 6 and 7, respectively. Each set of compounds 6 and 7 were alkylated with different alkyl halides and obtained respective products 8 and 9. All the products were screened for cytotoxicity against four human cancer cell lines such as A549-Lung (CCL-185), MCF7-Breast (HTB-22), DU145-Prostate (HTB-81) and HeLa-Cervical (CCL-2), compounds 9d, 9e and 9f which showed promising activity have been identified. The products were also screened for antimicrobial, anti bio-film and MBC activities. Promising compounds in each case have been identified.     

Synthesis and antitubercular evaluation of amidoalkyl dibenzofuranols and 1H-benzo[2,3]benzofuro[4,5-e][1,3]oxazin-3(2H)-ones

A new class of amidoalkyl dibenzofuranols and 1H-benzo[2,3]benzofuro[4,5-e][1,3]oxazin-3(2H)-ones was synthesized in very good yields through polyphosphoric acid supported on silica (PPA-SiO₂) catalyzed one-pot three component condensation of 2-dibenzofuranol; aromatic aldehydes and acetamide or benzamide or urea under solvent free conditions. At 125 °C the reaction led to the formation of amidoalkyl dibenzofuranols 5a-k where as at 160 °C cyclization take place to give oxazin-3(2H)-one analogues 6a-e. Screening all the 16 compounds for in vitro antimycobacterial activity against Mycobacterium tuberculosis H37Rv (MTB) resulted 1-((4-chlorophenyl)(2-hydroxydibenzo[b,d]furanyl)methyl)urea 5h; 1-((4-bromophenyl)(2-hydroxydibenzo[b,d]furanyl)methyl)urea 5i; 1-phenyl-1H-benzo[2,3]benzo furo[4,5-e][1,3]oxazin-3(2H)-one 6a (MIC 3.13 μg/mL) and 1-(4-chlorophenyl)-1H-benzo[2,3]benzofuro[4,5-e][1,3]oxazin-3(2H)-one 6b; 1-(4-bromophenyl)-1H-benzo[2,3]benzofuro [4,5-e][1,3]oxazin-3(2H)-one 6c (MIC 1.56 μg/mL) as most active antitubercular agents.     

Design,synthesis, and evaluation of novel VEGFR2 kinase inhibitors: Discovery of [1,2,4]triazolo[1,5-a]pyridine derivatives with slow dissociation kinetics

For the purpose of discovering novel type-II inhibitors of vascular endothelial growth factor receptor 2 (VEGFR2) kinase, we designed and synthesized 5,6-fused heterocyclic compounds bearing a anilide group. A co-crystal structure analysis of imidazo[1,2-b]pyridazine derivative 2 with VEGFR2 revealed that the N1-nitrogen of imidazo[1,2-b]pyridazine core interacts with the backbone NH group of Cys919. To retain this essential interaction, we designed a series of imidazo[1,2-a]pyridine, [1,2,4]triazolo[1,5-a]pyridine, thiazolo[5,4-b]pyridine, and 1,3-benzothiazole derivatives maintaining a ring nitrogen as hydrogen bond acceptor (HBA) at the corresponding position. All compounds thus designed displayed strong inhibitory activity against VEGFR2 kinase, and the [1,2,4]triazolo[1,5-a]pyridine 13d displayed favorable physicochemical properties. Furthermore, 13d inhibited VEGFR2 kinase with slow dissociation kinetics and also inhibited platelet-derived growth factor receptor (PDGFR) kinases. Oral administration of 13d showed potent anti-tumor efficacy in DU145 and A549 xenograft models in nude mice.     

Structure-based design,synthesis, and biological evaluation of imidazo[1,2-b]pyridazine-based p38 MAP kinase inhibitors

We identified novel potent inhibitors of p38 MAP kinase using structure-based design strategy. X-ray crystallography showed that when p38 MAP kinase is complexed with TAK-715 (1) in a co-crystal structure, Phe169 adopts two conformations, where one interacts with 1 and the other shows no interaction with 1. Our structure-based design strategy shows that these two conformations converge into one via enhanced protein-ligand hydrophobic interactions. According to the strategy, we focused on scaffold transformation to identify imidazo[1,2-b]pyridazine derivatives as potent inhibitors of p38 MAP kinase. Among the herein described and evaluated compounds, N-oxide 16 exhibited potent inhibition of p38 MAP kinase and LPS-induced TNF-α production in human monocytic THP-1 cells, and significant in vivo efficacy in rat collagen-induced arthritis models. In this article, we report the discovery of potent, selective and orally bioavailable imidazo[1,2-b]pyridazine-based p38 MAP kinase inhibitors with pyridine N-oxide group.