Imidazolyl benzimidazoles and imidazo[4,5-b]pyridines as potent p38α MAP kinase inhibitors with excellent in vivo antiinflammatory properties

Mader, Mary M.; Dios, Alfonso De; Shih, Chuan; Bonjouklian, Rosanne; Li, Tiechao; White, W. Hunter; Uralde, Beatriz López de; Sánchez-Martínez, Concepción; Prado, Miriam Del; Jaramillo, Carlos; Diego, Eugenio de; Cabrejas, L. M. Martin; Domı́nguez, Carmen; Montero, Carlos Closa; Shepherd, Timothy A.; Dally, Robert; Toth, John E.; Chatterjee, Arindam; Pleite, Sehila; Blanco‐Urgoiti, Jaime; Perez, Leticia; Barberis, Mario; Lorite, María J.; Jambrina, Enrique; Nevill, C. Richard; Lee, Paul A.; Schultz, Richard C.; Wolos, Jeffrey A.; Li, Li C.; Campbell, Robert M.; Anderson, Bryan D.

doi:10.1016/j.bmcl.2007.10.106

Cited by 110 publications

(33 citation statements)

References 12 publications

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“…Following an extensive medicinal chemistry effort to identify potent, selective, and orally active inhibitors of p38 MAPK (38,39), a series of trisubstituted imidazole derivatives were synthesized and tested. This effort resulted in the synthesis of LY2228820 and, for the first time, characterization of its crystal structure in complex with p38a MAPK.…”

Section: Discussionmentioning

confidence: 99%

Characterization of LY2228820 Dimesylate, a Potent and Selective Inhibitor of p38 MAPK with Antitumor Activity

Campbell

Anderson

Brooks

et al. 2014

Molecular Cancer Therapeutics

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104

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p38a mitogen-activated protein kinase (MAPK) is activated in cancer cells in response to environmental factors, oncogenic stress, radiation, and chemotherapy. p38a MAPK phosphorylates a number of substrates, including MAPKAP-K2 (MK2), and regulates the production of cytokines in the tumor microenvironment, such as TNF-a, interleukin-1b (IL-1b), . p38a MAPK is highly expressed in human cancers and may play a role in tumor growth, invasion, metastasis, and drug resistance. LY2228820 dimesylate (hereafter LY2228820), a trisubstituted imidazole derivative, is a potent and selective, ATP-competitive inhibitor of the a-and b-isoforms of p38 MAPK in vitro (IC 50 ¼ 5.3 and 3.2 nmol/L, respectively). In cellbased assays, LY2228820 potently and selectively inhibited phosphorylation of MK2 (Thr334) in anisomycinstimulated HeLa cells (at 9.8 nmol/L by Western blot analysis) and anisomycin-induced mouse RAW264.7 macrophages (IC 50 ¼ 35.3 nmol/L) with no changes in phosphorylation of p38a MAPK, JNK, ERK1/2, c-Jun, ATF2, or c-Myc 10 mmol/L. LY2228820 also reduced TNF-a secretion by lipopolysaccharide/IFNg-stimulated macrophages (IC 50 ¼ 6.3 nmol/L). In mice transplanted with B16-F10 melanoma, tumor phospho-MK2 (p-MK2) was inhibited by LY2228820 in a dose-dependent manner [threshold effective dose (TED) 70 ¼ 11.2 mg/kg]. Significant target inhibition (>40% reduction in p-MK2) was maintained for 4 to 8 hours following a single 10 mg/kg oral dose. LY2228820 produced significant tumor growth delay in multiple in vivo cancer models (melanoma, non-small cell lung cancer, ovarian, glioma, myeloma, breast). In summary, LY2228820 is a p38 MAPK inhibitor, which has been optimized for potency, selectivity, drug-like properties (such as oral bioavailability), and efficacy in animal models of human cancer. Mol Cancer Ther; 13(2); 364-74. Ó2013 AACR.

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Section: Discussionmentioning

confidence: 99%

Characterization of LY2228820 Dimesylate, a Potent and Selective Inhibitor of p38 MAPK with Antitumor Activity

Campbell

Anderson

Brooks

et al. 2014

Molecular Cancer Therapeutics

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104

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“…Starting from 2,3/3,4-diaminobenzoic acid (2), the synthetic route of the 2-substituent-1H-benzimidazole-4-carboxylic acids (6)(7)(8)(9)(10)(11)(12)(13)(14)(15) is shown in Scheme 1. 2-Substituent-1H-benzimidazole-4-carboxylic acids (6-13) were obtained by condensation of 2,3/3,4-diaminobenzoic acid (2) with aryl and heteroaryl aldehydes in the presence of 1,4-benzoquinone.…”

Section: Methodsmentioning

confidence: 99%

“…1,2,4-Oxadiazoles (21)(22)(23)(24)(25)(26)(27)(28)(29)(30) were obtained by the treatment of compounds (6)(7)(8)(9)(10)(11)(12)(13)(14)(15) with N-hydroxyacetamidine under EDC/ HOBT conditions. The acid hydrazides (18) was treated with acetic acid in the presence of phosphorus oxychloride afforded 1,3,4-oxadiazoles (31-32).…”

Section: Methodsmentioning

confidence: 99%

“…1 Benzimidazole derivatives are structural isosteres of naturally occurring nucleotides, which allows them to interact easily with the biopolymers of the living systems. Therefore, benzimidazole derivatives have shown different therapeutic properties such as antiulcer, 2 antihelminthic, 3 antihypertensive, 4 anticoagulant, 5 antiallergic, 6 analgesic, 7 anti-inflammatory, 8 antimicrobial, 9 antiviral, 10 antiparasitic, 11 and antioxidant.…”

Section: Introductionmentioning

confidence: 99%

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Synthesis and Biological Evaluation of Novel Benzimidazole Derivatives Bearing a Heterocyclic Ring at 4/5 Position

Wubulikasimu¹,

Yang²,

Xue³

et al. 2013

Bulletin of the Korean Chemical Society

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A series of novel benzimidazole derivatives bearing a heterocyclic ring as oxadiazole (21-32), thiadiazole (33-34), triazole (35-36) were synthesized and evaluated for their activities against Coxsackie virus B3 and B6 in Vero cells. Compounds 21-26, 31-36 with moieties of 2'-pyridyl, 3'-pyridyl and 4'-pyridyl at the 2-position and oxadiazoles, thiadiazole, or triazole substituent at the 4-or 5-position generally displayed activities against CVB3 and CVB6. Especially compound 24 (IC 50 = 1.08 µg/mL, SI = 61.7 against CVB3) was the promising candidate as lead compound for anti-enteroviral drug. It was observed in the incorporation of heterocyclic rings in benzimidazole at the 5-position could enhance their biological activities.

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“…1 In particular, they are a common heterocyclic scaffold in biologically active and medicinally significant compounds 2a and are found in a large variety of natural products. 2b Moreover, these groups of heterocyclic compounds exhibit a wide range of pharmacological properties, which include antiviral, 3 antimicrobial, 4 antitumor, 5 antibiotic, 6 antifungal, 7 anticonvulsant, 8 anti-inflammatory activity 9 and many others. 10,11 Their use in the field of advanced materials is also worthy of note.…”

Section: Introductionmentioning

confidence: 99%

The efficient o-benzenedisulfonimide catalysed synthesis of benzothiazoles, benzoxazoles and benzimidazoles

Barbero¹,

Cadamuro²,

Dughera³

2012

Arkivoc

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o-Benzenedisulfonimide has been used to efficiently catalyse the reaction between 2-aminothiophenol, 2-aminophenol, o-phenylenediamine and various ortho esters (28 examples; average yield 90%) or aldehydes (17 examples; average yield 72%) giving the corresponding benzofused azoles in excellent yields. Reaction conditions were very simple. In addition, other carboxylic acid derivatives have been tested and gave good results. The catalyst was easily recovered and reused.

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Imidazolyl benzimidazoles and imidazo[4,5-b]pyridines as potent p38α MAP kinase inhibitors with excellent in vivo antiinflammatory properties

Cited by 110 publications

References 12 publications

Characterization of LY2228820 Dimesylate, a Potent and Selective Inhibitor of p38 MAPK with Antitumor Activity

Characterization of LY2228820 Dimesylate, a Potent and Selective Inhibitor of p38 MAPK with Antitumor Activity

Synthesis and Biological Evaluation of Novel Benzimidazole Derivatives Bearing a Heterocyclic Ring at 4/5 Position

The efficient o-benzenedisulfonimide catalysed synthesis of benzothiazoles, benzoxazoles and benzimidazoles

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