共查询到20条相似文献,搜索用时 15 毫秒
1.
Allen SH Johns BA Gudmundsson KS Freeman GA Boyd FL Sexton CH Selleseth DW Creech KL Moniri KR 《Bioorganic & medicinal chemistry》2006,14(4):944-954
A novel series of potent C-6 substituted pyrazolo[1,5-a]pyridine inhibitors of herpes simplex viruses has been identified. A synthetic methodology was developed involving functionalization of a C-6 trifluoromethyl pyrazolo[1,5-a]pyridine to allow facile access to a diverse set of analogues from common late stage intermediates. The expansion of the SAR of this series at the 6 position allows for modifications to developability parameters such as clogP, while maintaining potency comparable to acyclovir. 相似文献
2.
Ismail MA Arafa RK Wenzler T Brun R Tanious FA Wilson WD Boykin DW 《Bioorganic & medicinal chemistry》2008,16(2):683-691
The key dinitrile intermediates 4a-d were synthesized by reaction of phenacyl bromide 1 and the appropriate 2-amino-5-bromopyridines to yield 3a-d. Suzuki coupling of 3a-d with 4-cyanophenylboronic acid yielded the 2,6-bis(4-cyanophenyl)-imidazo[1,2-a]pyridine derivatives 4a-d. The bis-amidoximes 5a-d, obtained from 4a-d by the action of hydroxylamine, were converted to the bis-O-acetoxyamidoximes which on catalytic hydrogenation in a mixture of ethanol/ethyl acetate gave the acetate salts of 2,6-bis[4-(amidinophenyl)]-imidazo[1,2-a]pyridines 7a-d. In contrast, catalytic hydrogenation of the bis-O-acetoxyamidoxime of 5a in glacial acetic acid gave the saturated analogue 2,6-bis[4-(amidinophenyl)]-5,6,7,8-tetrahydro-imidazo[1,2-a]pyridine 8. O-Methylation of the amidoximes 5a-d gave the N-methoxyamidines 6a-d. The diamidines showed strong DNA binding affinity, were very active in vitro against T. b. r. exhibiting IC(50) values between 7 and 38nM, but were less effective against P. f. with IC(50) values between 23 and 92nM. Two of the diamidines 7c and 7d were slightly more active than furamidine but less active than azafuramidine in the T. b. r. STIB900 mouse model. Only one prodrug 6b showed moderate activity in the same mouse model. 相似文献
3.
Aaron Smith Zhi-Jie Ni Daniel Poon Zilin Huang Zheng Chen Qiong Zhang Laura Tandeske Hanne Merritt Kevin Shoemaker John Chan Susan Kaufman Kay Huh Jeremy Murray Brent A. Appleton Sandra W. Cowan-Jacob Clemens Scheufler Takanori Kanazawa Johanna M. Jansen Cynthia M. Shafer 《Bioorganic & medicinal chemistry letters》2017,27(23):5221-5224
A series of imidazo[1,2-a]pyridin-6-yl-benzamide analogs was designed as inhibitors of B-RAFV600E. Medicinal chemistry techniques were employed to explore the SAR for this series and improve selectivity versus P38 and VEGFR2. 相似文献
4.
Anderson M Beattie JF Breault GA Breed J Byth KF Culshaw JD Ellston RP Green S Minshull CA Norman RA Pauptit RA Stanway J Thomas AP Jewsbury PJ 《Bioorganic & medicinal chemistry letters》2003,13(18):3021-3026
High-throughput screening identified the imidazo[1,2-a]pyridine and bisanilinopyrimidine series as inhibitors of the cyclin-dependent kinase CDK4. Comparison of their experimentally-determined binding modes and emerging structure-activity trends led to the development of potent and selective imidazo[1,2-a]pyridine inhibitors for CDK4 and in particular CDK2. 相似文献
5.
Hiroyuki Kishino Minoru Moriya Shunji Sakuraba Toshihiro Sakamoto Hidekazu Takahashi Takao Suzuki Ryuichi Moriya Masahiko Ito Hisashi Iwaasa Norihiro Takenaga Akane Ishihara Akio Kanatani Nagaaki Sato Takehiro Fukami 《Bioorganic & medicinal chemistry letters》2009,19(16):4589-4593
A series of imidazo[1,2-a]pyridine derivatives was identified and evaluated for MCH1R binding and antagonistic activity. Introduction of a methyl substituent at the 3-position of imidazo[1,2-a]pyridine provided compounds with a significant improvement in MCH1R affinity. Representative compounds in this series exhibited good potency and brain exposure in rats. 相似文献
6.
Byth KF Culshaw JD Green S Oakes SE Thomas AP 《Bioorganic & medicinal chemistry letters》2004,14(9):2245-2248
Exploration of SAR and optimisation of the imidazo[1,2-a]pyridine CDK inhibitors has lead to the discovery of novel, potent and selective inhibitors of the cyclin-dependent kinase CDK2. Understanding of SAR has identified positions of substitution, which allow modification of physical properties and offer the potential for in vivo optimisation. 相似文献
7.
《Bioorganic & medicinal chemistry letters》2014,24(19):4650-4653
We report the design, synthesis, and biological evaluation of imidazopyridine-based peptidomimetics based on the substrate consensus sequence of Akt, an AGC family serine/threonine kinase hyperactivated in over 50% of human tumors. Our ligand-based approach led to the identification of novel substrate mimetic inhibitors of Akt1 featuring an unnatural extended dipeptide surrogate. Compound 11 inhibits Akt isoforms in the sub-micromolar range and exhibits improved proteolytic stability relative to a parent pentapeptide. 相似文献
8.
Martínez González S Hernández AI Varela C Rodríguez-Arístegui S Alvarez RM García AB Lorenzo M Rivero V Oyarzabal J Rabal O Bischoff JR Albarrán M Cebriá A Alfonso P Link W Fominaya J Pastor J 《Bioorganic & medicinal chemistry letters》2012,22(5):1874-1878
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. 相似文献
9.
Yoshito Terao Hideo Suzuki Masato Yoshikawa Hiroaki Yashiro Shiro Takekawa Yasushi Fujitani Kengo Okada Yoshihisa Inoue Yoshio Yamamoto Hideyuki Nakagawa Shuhei Yao Tomohiro Kawamoto Osamu Uchikawa 《Bioorganic & medicinal chemistry letters》2012,22(24):7326-7329
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. 相似文献
10.
Spasov A. A. Zhukovskaya O. N. Gurova N. A. Naumenko L. V. Eliseeva N. V. Kucheryavenko A. F. Kosolapov V. A. Yakovlev D. S. Muravyeva V. Y. Babkova V. A. Babkov D. A. Lifanova J. V. Morkovnik A. S. 《Russian Journal of Bioorganic Chemistry》2022,48(2):281-291
Russian Journal of Bioorganic Chemistry - Halides of 2-aminobenzimidazolium and derivatives of 9-substituted 2-(4-fluorophenyl)imidazo[1,2-a]benzimidazoles have been studied for ten types of... 相似文献
11.
Kristjan S. Gudmundsson Brian A. Johns Jason Weatherhead 《Bioorganic & medicinal chemistry letters》2009,19(19):5689-5692
Synthesis of several pyrazolo[1,5-c]pyrimidines, pyrazolo[1,5-a]pyrimidines and pyrazolo[1,5-a][1,3,5]triazines with potent activity against herpes simplex viruses is described. Synthetic approaches allowing for variation of the substitution pattern are outlined and resulting changes in antiviral activity are highlighted. Several compounds with in vitro antiviral activity similar or better than acyclovir are described. 相似文献
12.
Blackaby WP Atack JR Bromidge F Castro JL Goodacre SC Hallett DJ Lewis RT Marshall GR Pike A Smith AJ Street LJ Tattersall DF Wafford KA 《Bioorganic & medicinal chemistry letters》2006,16(5):1175-1179
Imidazo[1,2-a]pyrimidines are GABA(A) receptor benzodiazepine binding site ligands which can exhibit functional selectivity for the alpha(3) subtype over the alpha(1) subtype. SAR studies to optimize this functional selectivity are described. 相似文献
13.
《Nucleosides, nucleotides & nucleic acids》2013,32(10):1907-1917
Abstract 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 µM) at non-cytotoxic concentrations. 相似文献
14.
Zimmermann PJ Buhr W Brehm C Palmer AM Feth MP Senn-Bilfinger J Simon WA 《Bioorganic & medicinal chemistry letters》2007,17(19):5374-5378
A series of novel 8-indanylamino- and 8-indanyloxy-substituted imidazo[1,2-a]pyridines with reduced lipophilicity was synthesized from easily accessible starting compounds. The anti-secretory activity of these compounds has been assessed in a competitive binding assay against H(+)/K(+)-ATPase from hog gastric mucosa. Some of the compounds proved to be potent inhibitors of the gastric acid pump. 相似文献
15.
Katherine A. Abrahams Jonathan A. G. Cox Vickey L. Spivey Nicholas J. Loman Mark J. Pallen Chrystala Constantinidou Raquel Fernández Carlos Alemparte Modesto J. Remui?án David Barros Lluis Ballell Gurdyal S. Besra 《PloS one》2012,7(12)
Mycobacterium tuberculosis is a major human pathogen and the causative agent for the pulmonary disease, tuberculosis (TB). Current treatment programs to combat TB are under threat due to the emergence of multi-drug and extensively-drug resistant TB. Through the use of high throughput whole cell screening of an extensive compound library a number of imidazo[1,2-a]pyridine (IP) compounds were obtained as potent lead molecules active against M. tuberculosis and Mycobacterium bovis BCG. The IP inhibitors (1–4) demonstrated minimum inhibitory concentrations (MICs) in the range of 0.03 to 5 µM against a panel of M. tuberculosis strains. M. bovis BCG spontaneous resistant mutants were generated against IP 1, 3, and 4 at 5× MIC and subsequent whole genome sequencing identified a single nucleotide polymorphism 937ACC>937GCC (T313A) in qcrB, which encodes the b subunit of the electron transport ubiquinol cytochrome C reductase. This mutation also conferred cross-resistance against IP 1, 3 and 4 demonstrating a common target. Gene dosage experiments confirmed M. bovis BCG QcrB as the target where over-expression in M. bovis BCG led to an increase in MIC from 0.5 to >8 µM for IP 3. An acute murine model of TB infection established bacteriostatic activity of the IP series, which await further detailed characterization. 相似文献
16.
Novel hexahydroimidazo[1,2-a]pyridines prepared by the addition of ethyl (1-benzylimidazolidin-2-ylidene)acetate (2) to the fungal metabolite podoscyphic acid (1a) and esters of 1a have been evaluated for their ability to inhibit the inducible TNF-alpha promoter activity in T cells. The methyl ester 3b is the most potent, inhibiting the TNF-alpha driven reporter gene expression in Jurkat T cells with an IC(50)-value of 2.0 microg/ml (3.6 microM). In addition, compound 3b inhibited the inducible TNF-alpha production in the myelomonocytic U937 cells with an IC(50)-value of 4.6 microM. 相似文献
17.
A. Gueiffier Y. Blache J. P. Chapat A. Elhakmaoui E. M. Essassi G. Andrei 《Nucleosides, nucleotides & nucleic acids》2013,32(3-5):551-554
Abstract Synthesis of acyclo-C-nucleoside derivatives in the imidazo[1,2-a]pyrimidine series was reported. None of the evaluated compounds showed appreciable antiviral activity. 相似文献
18.
《Bioorganic & medicinal chemistry》2020,28(16):115584
Triple-negative breast cancer (TNBC), a subset of breast cancers, have poorer survival than other breast cancer types. Recent studies have demonstrated that the abnormal Hedgehog (Hh) pathway is activated in TNBC and that these treatment-resistant cancers are sensitive to inhibition of the Hh pathway. Smoothened (Smo) protein is a vital constituent in Hh signaling and an attractive drug target. Vismodegib (VIS) is one of the most widely studied Smo inhibitors. But the clinical application of Smo inhibitors is limited to adult patients with BCC and AML, with many side effects. Therefore, it’s necessary to develop novel Smo inhibitor with better profiles. Twenty [1,2,4]triazolo[4,3-a]pyridines were designed, synthesized and screened as Smo inhibitors. Four of these novel compounds showed directly bound to Smo protein with stronger binding affinity than VIS. The new compounds showed broad anti-proliferative activity against cancer cell lines in vitro, especially triple-negative breast cancer cells. Mechanistic studies demonstrated that TPB15 markedly induced cell cycle arrest and apoptosis in MDA-MB-468 cells. TPB15 blocked Smo translocation into the cilia and reduced Smo protein and mRNA expression. Furthermore, the expression of the downstream regulatory factor glioma-associated oncogene 1 (Gli1) was significantly inhibited. Finally, TPB15 demonstrated greater anti-tumor activity in our animal models than VIS with lower toxicity. Hence, these results support further optimization of this novel scaffold to develop improved Smo antagonists. 相似文献
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20.
Cheung M Harris PA Badiang JG Peckham GE Chamberlain SD Alberti MJ Jung DK Harris SS Bramson NH Epperly AH Stimpson SA Peel MR 《Bioorganic & medicinal chemistry letters》2008,18(20):5428-5430
A series of pyrazolo[1,5-a]pyridine derivatives was designed and synthesized as novel potent p38 kinase inhibitors. Our approaches towards improving in vitro metabolism and in vivo pharmacokinetic properties of the series are described. 相似文献