ABSTRACT
Diabetes mellitus is a chronic, complex and multifactorial disease associated characteristically with hyperglycemia. One of the most recently approved antidiabetic drug classes for clinical use are sodium-glucose cotransporter type 2 (SGLT-2) inhibitors. SGLT-2 is a protein expressed in the kidneys, responsible for glucose reabsorption from the glomerular filtrate to the plasma. It is known, nowadays, that diabetic patients show an increased glucose renal reabsorption capacity, caused by the overexpression of the SGLT-2 transporter, thus contributing to hyperglycemia. From establishing this correlation, the SGLT-2 transporter started to be considered as a therapeutic target of interest, culminating in the approval of the first antidiabetic SGLT-2 inhibitor, dapagliflozin (Forxiga® or Farxiga®, Bristol-Myers Squibb & AstraZeneca), in 2012 in Europe. On the other hand, canagliflozin (Invokana®, Janssen Pharmaceutical) was the first drug in this class to be approved by the FDA, the U.S. Food and Drug Administration, in 2013. This review concerns the discovery and development of the first representatives of this class of antidiabetic drugs, and the description of new optimized analogues that are currently in the clinical and preclinical stages of development.
ABSTRACT
Cancer incidence represents an important public health problem worldwide. Nuclear factor kappa B (NF- κB) transcription factor plays a pivotal role in the regulation of genes that control various responses in eukaryotic cells, including proliferation and survival, cytoskeletal remodeling, cellular adhesion and apoptosis. Extensive studies have demonstrated the contribution of NF-κB transcription in the promotion and progression of several hematological malignancies and solid tumors, in which NF-κB constitutive activation and/or overexpression are common clinical features. Moreover, triggering the NF-κB pathway is already considered one of the important mechanisms of resistance development to chemotherapy and radiotherapy, indicating that the inhibition of this signaling cascade is a promising approach to enhancing efficacy and preventing acquired resistance in cancer treatment. In this review, research efforts dedicated to the identification of novel NF-κB signaling pathway inhibitors as promising anticancer drug candidates are described.
Subject(s)
Antineoplastic Agents/pharmacology , NF-kappa B/antagonists & inhibitors , NF-kappa B/metabolism , Neoplasms/drug therapy , Signal Transduction/drug effects , Animals , Anti-Inflammatory Agents, Non-Steroidal/pharmacology , Antineoplastic Agents/chemistry , Glucocorticoids/pharmacology , Humans , I-kappa B Kinase/antagonists & inhibitors , Neoplasms/genetics , Neoplasms/metabolism , Proteasome Endopeptidase Complex/metabolism , Ubiquitination/drug effectsABSTRACT
In this paper, we report the synthesis and pharmacological evaluation of pyrazine N-acylhydrazone (NAH) derivatives (2a-s) designed as novel analgesic and anti-inflammatory drug candidates. This series was planned by molecular simplification of prototype 1 (LASSBio-1018), previously described as a non-selective cyclooxygenase inhibitor. Derivatives 2a-s were evaluated in several animal models of pain and inflammation, standing-out compound 2o (2-N'-[(E)-(3,4,5-trimethoxyphenyl) methylidene]-2-pyrazinecarbohydrazide; LASSBio-1181), that was also active in a murine model of chronic inflammation (i.e., adjuvant-induced arthritis test in rats) and can be considered a new analgesic and anti-inflammatory lead for drug development.
