Zürcher G, Colzi A, Da Prada M
Pharmaceutical Research Department, F. Hoffmann-La Roche Ltd, Basel, Switzerland.
J Neural Transm Suppl. 1990;32:375-80. doi: 10.1007/978-3-7091-9113-2_51.
A random biochemical screening followed by lead optimization culminated in the discovery of Ro 40-7592 3,4-dihydroxy-4'-methyl-5-nitrobenzophenone). Ro 40-7592 was found to inhibit COMT in a competitive fashion both in the CNS and in the periphery (Ki for the liver enzyme = 30 nM). Ro 40-7592 (30 mg/kg p.o.) combined with benserazide (15 mg/kg p.o.) and a low dose of L-DOPA (10 mg/kg p.o.) almost completely blocked (for about 6 h) the formation of 3-O-methyldopa (3-OMD) in brain and plasma, producing a long-lasting increase of L-DOPA in plasma and a parallel marked increase of L-DOPA and dopamine in the brain. Ro 40-7592, combined with peripheral decarboxylase inhibitors and L-DOPA (as in Madopar and Sinemet), will offer substantial advantages in the therapy of Parkinson's disease, i.e. enhanced bioavailability and prolonged plasma half-life of L-DOPA, pronounced DOPA sparing effect and blockade of 3-OMD formation.
通过随机生化筛选并进行先导化合物优化，最终发现了Ro 40-7592（3,4-二羟基-4'-甲基-5-硝基二苯甲酮）。研究发现，Ro 40-7592在中枢神经系统和外周均以竞争性方式抑制儿茶酚-O-甲基转移酶（COMT）（肝脏酶的Ki = 30 nM）。Ro 40-7592（口服30 mg/kg）与苄丝肼（口服15 mg/kg）和低剂量左旋多巴（口服10 mg/kg）联合使用，几乎完全阻断（约6小时）脑和血浆中3-O-甲基多巴（3-OMD）的形成，使血浆中左旋多巴持续增加，同时脑内左旋多巴和多巴胺也显著增加。Ro 40-7592与外周脱羧酶抑制剂和左旋多巴联合使用（如在美多芭和息宁中），将在帕金森病治疗中带来显著优势，即提高左旋多巴的生物利用度和延长血浆半衰期，显著的多巴节省效应以及阻断3-OMD的形成。
