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Discovery and Development of GCC1290K, a novel drug candidate for the treatment of Parkinson's disease

2008년 8월 11일 22시 24분 25초
목18G2심 이곳을 클릭하시면 발표코드에 대한 설명을 보실 수 있습니다.
목 14시 : 40분
의약화학 - Recent Drug Development of Neurodegenerative Disease
저자 및
녹십자(주), Korea
The development and progression of Parkinson's disease, a neurodegenerative disease are poorly addressed by known drug therapies and represent major unmet medical needs. Parkinson's disease is a progressive neurodegenerative disease characterized by loss of dopaminergic neurons in the substantia nigra. Even though the cause of neuronal loss is not understood, the resulting loss of motor control can be temporarily improved by treatment with the dopamine precursor, L-3,4-dihydroxyphenylalanine (L-DOPA). However, motor fluctuations limit this therapeutic approach for most patients. There are recent reports that dextromethorphan (DM), an active ingredient in a variety of widely used anticough remedies, protected dopaminergic neurons in rat primary mesencephalic neuron-glia cultures against lipopolysaccharide (LPS)-mediated degeneration and provided potent protection for dopaminergic neurons in a MPTP mouse model. The underlying mechanism for the protective effect of DM was attributed to its anti-inflammatory activity through inhibition of microglia activation. In an effort to develop more potent compounds for the treatment of PD, Kim's group at Kangwon National University have screened a series of analogs of DM, and 3-hydroxymorphinan (3-HM) emerged as a promising candidate for this purpose. In spite of good efficacy of 3-HM against a MPTP mouse model, poor PK of 3-HM prohibits its candidacy of orally available drug development. In an effort to improve PK and efficacy, we designed and screened a variety of prodrugs of 3-HM. Eventually we discovered GCC1290K as a novel drug candidate for a promising anti-Parkinsonian agent. Here we will discuss biological aspects as well as medicinal and process chemistry regarding GCC1290K.