Design and development of biological response modifiers

点击翻译按钮获取中文摘要

Various biological response modifiers, including nuclear receptor ligands (agonists/antagonists) and enzyme inhibitors, were designed and prepared, aiming development of agents for the treatment of chronic diseases (cancers, diabetes, rheumatoid diseases etc). Methodologically, functional regulation hypothesis of nuclear receptors based on the lingand-dependent conformational change of their substructure, helix 12, and multi-template hypothesis have been proposed. Based on these hypotheses,(1)ligands (agonists and antagonists) of nuclear receptors [retinoic acid receptors (RARs), retinoid X receptors (RXRs), androgen receptor, progesterone receptor, estrogen receptor, peroxisome proliferators-activated receptors (PPARs), farnsoid X receptor (FXR), liver X receptors (LXRs), and viamine D receptor,(2)specfic and potent inhibitors of tumor necrosis factor (TNF)-α production, tubulin polymerization, puromycin-sensitive aminopeptidase (PSA), α-glucosidase, dipeptidylpeptidase (DPP) type IV, … More tumor cell invasion, histone deacetylase (HDAC), heparanase, calcineulin, cyclooxygenase (COX), nitrogen oxidase synthase (NOS), μ-calpain, thymidine phosphorylase, and angiogenesis, have been created.Typical compounds created in this research project includes;(a)a synthetic retinoid, Am80 (tamibarotene), which has been launched since 2005 as a medicament for the treatment of acute promyelocytic leukemia, and is now under phase II clinical trial for the treatment of Crohn's diseases,(b)a synthetic retinoid, TAC-101, which is now under phase III clinical trial for the treatment of liver cancer,(c)non-steroidal/non-anilide type structure of androgen antagonists which are active toward so-called anti-androgen-resistant cells (ex.LNCaP cells) bearing point mutated androgen receptor(s),(d)novel vitamin D antagonists (DLAMs) containing a nitrogen atom in their structure,(e)steroid hormone receptor ligands containing a carborane group in their structure.Our studies suggests the wide utility/applicability of the above-mentioned hypothesis for drug design, and the usefulness of thalidomide-related phthalimide/homophtalimide skeleton and diphenylpentane structure as the scaffold of various biologically active compounds and steroid-related active compounds, respectively. Less