Laboratory of Chemistry, BIAL, A Avenida da Siderurgia Nacional, 4745-457 S. Mamede do Coronado, Portugal.
J Med Chem. 2010 Apr 22;53(8):3396-411. doi: 10.1021/jm1001524.
Novel nitrocatechol-substituted heterocycles were designed and evaluated for their ability to inhibit catechol-O-methyltransferase (COMT). Replacement of the pyrazole core of the initial hit 4 with a 1,2,4-oxadiazole ring resulted in a series of compounds endowed with longer duration of COMT inhibition. Incorporation of a pyridine N-oxide residue at position 3 of the 1,2,4-oxadiazole ring led to analogue 37f, which was found to possess activity comparable to entacapone and lower toxicity in comparison to tolcapone. Lead structure 37f was systematically modified in order to improve selectivity and duration of COMT inhibition as well as to minimize toxicity. Oxadiazole 37d (2,5-dichloro-3-(5-(3,4-dihydroxy-5-nitrophenyl)-1,2,4-oxadiazol-3-yl)-4,6-dimethylpyridine 1-oxide (BIA 9-1067)) was identified as a long-acting, purely peripheral inhibitor, which is currently under clinical evaluation as an adjunct to L-Dopa therapy of Parkinson's disease.
新型含硝基儿茶酚取代杂环化合物被设计并评估其抑制儿茶酚-O-甲基转移酶（COMT）的能力。用 1,2,4-噁二唑环替代初始命中化合物 4 的吡唑核心，得到了一系列具有更长 COMT 抑制持续时间的化合物。在 1,2,4-噁二唑环的 3 位引入吡啶 N-氧化物残基得到类似物 37f，其被发现具有与恩他卡朋相当的活性，并且与托卡朋相比毒性更低。为了提高选择性、延长 COMT 抑制时间并最小化毒性，对先导化合物 37f 进行了系统修饰。噁二唑 37d（2,5-二氯-3-（5-（3,4-二羟基-5-硝基苯基）-1,2,4-噁二唑-3-基）-4,6-二甲基吡啶 1-氧化物（BIA 9-1067））被确定为一种长效、纯外周抑制剂，目前正在作为帕金森病的 L-Dopa 治疗的辅助药物进行临床评估。
