Thalidomide and Analogs as Anti-Inflammatory and Immunomodulator Drug Candidates

Lima, Lı́dia Moreira; Fraga, Carlos A.M.; Koatz, Vera Lúcia Gonçalves; Barreiro, Eliezer J.

doi:10.2174/187152306775537328

Cited by 6 publications

(13 citation statements)

References 71 publications

(206 reference statements)

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“…TNF-RI is constitutively expressed in most cells, but not in inactive T cells and erythrocytes; TNF-RII is expressed more often in hematopoietic and endothelial cells (Lima et al, 2006).…”

Section: Tumor Necrosis Factormentioning

confidence: 99%

“…This type of receptor is then able to recognize pathogen-associated molecular patterns (PAMPs), starting a cascade of signal transduction leading to the activation of transcription factors, such as the NF-κB (nuclear factor kappa B) (Zuany-Amorin et al, 2002;Lima et al, 2006).…”

Section: Tumor Necrosis Factormentioning

confidence: 99%

“…The human TNF-α is synthesized as a polypeptide precursor of 233 amino acid residues attached to the cell membrane and is released through regiospecific proteolysis between the amino acids Ala76 and Val77, producing the soluble form of the cytokine (Gearing et al, 1994;Lima et al, 2006;Mukhopadhyay et al, 2006;DasGupta et al, 2009). The enzyme responsible for the proteolytic cleavage of TNF-α anchored to the cell membrane was identified as a zinc-dependent metalloproteinase, denoted as tumor necrosis factor alpha converting enzyme (TACE) (Black et al, 1997;Moss et al, 1997).…”

Section: Tumor Necrosis Factormentioning

confidence: 99%

“…The identification of the promising anti-inflammatory and immunomodulatory properties of 3 resulted in its approval by the US-FDA in July 1998 for the treatment of moderate to severe cutaneous manifestations of lepromatous leprosy (Matthews, McCoy, 2003;Teo et al, 2005;Lima et al, 2006). After approval of thalidomide (3) for the treatment of erythema nodosum leprosum, a series of trials was initiated aimed at evaluating the therapeutic potential of 3 in the treatment of inflammatory and autoimmune diseases related to increased plasma concentrations of TNF-α, such as rheumatoid arthritis and Crohn's disease (Man et al, 2003;Matthews, McCoy, 2003).…”

Section: Thalidomide and Structural Analoguesmentioning

confidence: 99%

“…The transcription factor NF-kB plays a central role in inflammation and immune response, acting as a mediator both in TNF-α biosynthesis and in the biological response mediated by the binding of TNF-α to its target receptor (Hanada, Yoshimura, 2002;Lima et al, 2006;Paul et al, 2006). For this reason, the identification of small molecules that inhibit the NF-kB signaling pathway has emerged as a promising therapeutic approach for the treatment of inflammatory and autoimmune diseases (Hanada, Yoshimura, 2002;Palladino et al, 2003).…”

Section: Modulators Of Nf-kb Signaling Pathwaymentioning

confidence: 99%

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Therapeutic approaches for tumor necrosis factor inhibition

Barbosa

Fumian

Miranda

et al. 2011

Braz. J. Pharm. Sci.

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Tumor necrosis factor (TNF) consists of an inflammatory cytokine essential for homeostasis and organism defense. Despite its physiological relevance, both increased biosynthesis and release of TNF lead to the exacerbation of inflammatory and oxidative responses, which are related to the pathogenesis of a host of diseases of an inflammatory, autoimmune and/or infectious nature. In this context, effective therapeutic approaches for the modulation of TNF have been the focus of research efforts. Approximately one million individuals worldwide have been treated with biotechnological inhibitors of this cytokine, the so-called anti-TNF biopharmaceuticals. However, given the high risk of infection and the limitations related to cost and administration routes, new therapeutic approaches aimed at biological targets that directly or indirectly modulate the production and/or activation of TNF appear promising alternatives for the discovery of new anti-inflammatory and immunomodulatory orally active drugs and are therefore discussed in this paper.Uniterms: Tumor necrosis factor. TACE. p38 MAPK. NF-kB. cAMP. Phosphodiesterase. Adenosine receptor.O fator de necrose tumoral (do inglês, tumor necrosis factor -TNF) consiste em uma citocina inflamatória essencial para a homeostase e defesa do organismo. A despeito de sua relevância fisiológica, o aumento da biossíntese e liberação do TNF conduzem à exacerbação das respostas inflamatória e oxidativa, as quais estão relacionadas à patogênese de várias doenças de natureza inflamatória, auto-imune e/ou infecciosa. A busca por abordagens terapêuticas eficientes na modulação do TNF tem sido alvo de diversos esforços de pesquisa. Aproximadamente um milhão de pessoas ao redor do mundo já foi tratado com inibidores biotecnológicos desta citocina, os chamados biofármacos anti-TNF. Entretanto, em face ao elevado risco de infecções e as limitações relacionadas ao custo e a via de administração, novas abordagens terapêuticas com foco em alvos que modulem, de forma direta ou indireta, a produção e/ou ativação do TNF surgem como alternativas promissoras para a descoberta de novos fármacos antiinflamatórios e imunomoduladores ativos por via oral e serão discutidas neste trabalho. Unitermos: Fator de necrose tumoral. TACE. MAPK p38. NF-kB. AMPc. Fosfodiesterase. Receptor de adenosina.

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“…TNF-RI is constitutively expressed in most cells, but not in inactive T cells and erythrocytes; TNF-RII is expressed more often in hematopoietic and endothelial cells (Lima et al, 2006).…”

Section: Tumor Necrosis Factormentioning

confidence: 99%

Section: Tumor Necrosis Factormentioning

confidence: 99%

Section: Tumor Necrosis Factormentioning

confidence: 99%

Section: Thalidomide and Structural Analoguesmentioning

confidence: 99%

Section: Modulators Of Nf-kb Signaling Pathwaymentioning

confidence: 99%

See 3 more Smart Citations

Therapeutic approaches for tumor necrosis factor inhibition

Barbosa

Fumian

Miranda

et al. 2011

Braz. J. Pharm. Sci.

Self Cite

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Development of new CoMFA and CoMSIA 3D-QSAR models for anti-inflammatory phthalimide-containing TNFα modulators

Avila

Romeiro

Silva

et al. 2006

Bioorganic & Medicinal Chemistry

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Anti-inflammatory effects of LASSBio-998, a new drug candidate designed to be a p38 MAPK inhibitor, in an experimental model of acute lung inflammation

Lima

Machado

Simon

et al. 2011

Pharmacological Reports

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We investigated the effects of LASSBio-998 (L-998), a compound designed to be a p38 MAPK (mitogen-activated protein kinase) inhibitor, on lipopolysaccharide (LPS)-induced acute lung inflammation in vivo. BALB/c mice were challenged with aerosolized LPS inhalation (0.5 mg/ml) 4 h after oral administration of L-998. Three hours after LPS inhalation, bronchoalveolar lavage fluid was obtained to measure the levels of the proinflammatory cytokines TNF-α (tumor necrosis factor-α) and IL-1 (interleukin-1) and the chemokines MCP-1 (monocyte chemoattractant protein-1) and KC (keratinocyte chemoattractant). In addition, neutrophil infiltration and p38 MAPK phosphorylation was measured. L-998 inhibited LPS-induced production of TNF-α and IL-1β and did not alter KC and MCP-1 levels. Furthermore, L-998 also significantly decreased neutrophil accumulation in lung tissues. As expected, L-998 diminished p38 MAPK phosphorylation and reduced acute lung inflammation. Inhibition of p38 MAPK phosphorylation by L-998 was also demonstrated in LPS-challenged murine C57BL/6 peritoneal macrophages in vitro, with concentration-dependent effects. L-998 suppressed LPS-induced lung inflammation, most likely by inhibition of the cytokine-p38 MAPK pathway, and we postulate that L-998 could be a clinically relevant anti-inflammatory drug candidate.

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Thalidomide and Analogs as Anti-Inflammatory and Immunomodulator Drug Candidates

Cited by 6 publications

References 71 publications

Therapeutic approaches for tumor necrosis factor inhibition

Therapeutic approaches for tumor necrosis factor inhibition

Development of new CoMFA and CoMSIA 3D-QSAR models for anti-inflammatory phthalimide-containing TNFα modulators

Anti-inflammatory effects of LASSBio-998, a new drug candidate designed to be a p38 MAPK inhibitor, in an experimental model of acute lung inflammation

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