Design And Development Of Experimental Therapeutics

实验疗法的设计和开发

• 批准号: 6667915
• 负责人: Nigel H. Greig
• 金额: --
• 依托单位: NATIONAL INSTITUTE ON AGING
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/6667915
• 关键词: Alzheimer's disease; Parkinson's disease; aging; brain disorder chemotherapy; cardiovascular agents; cardiovascular disorder chemotherapy; cardiovascular pharmacology; drug design /synthesis /production; drug screening /evaluation; endocrine pharmacology; human subject; human therapy evaluation; hypoglycemic agents; neuropharmacologic agent; neuropharmacology; noninsulin dependent diabetes mellitus; patient oriented research; stroke

Design and Development of Drugs and Pharmacologic Probes: The goal of the Drug Design & Development Section is to develop novel agents against pivotal steps involved in the pathophysiology of diseases associated with aging, with particular interest in neurological diseases, such as Alzheimer's disease (AD) and stroke, as well as in systemic diseases, such as diabetes. 1. Alzheimer's Disease: Three series of agents are being developed to treat AD. Selective inhibitors of acetylcholinesterase (AChE), of butyrylcholinesterase (BChE), and of amyloid-beta peptide (Ab) production. 1.1. Cholinesterase inhibitors: Compounds were developed to optimally augment the cholinergic system in the elderly and raise levels of the neurotransmitter, acetylcholine (ACh). Extensive studies involving chemistry, X-ray crystallography, biochemistry and pharmacology resulted in the design and synthesis of novel compounds to differentially inhibit either AChE or BChE in either the brain or periphery for an optimal duration for the potential treatment of a variety of diseases, such as AD, Myasthenia Gravis, and as chemical warfare prophylactics. 1.1A. AChE: Two of our numerous novel synthesized AChE inhibitors are in development for the treatment of AD; specifically, the pure non-competitive inhibitors, phenserine and tolserine. Both are phenylcarbamates of physostigmine that are 70- and 190-fold selective for AChE vs. BChE. Compared to current agents for AD treatment, they have a favorable toxicologic profile and robustly enhance cognition in animal models (undertaken in collaboration with Dr. Donald Ingram, NIA). They possess a long duration of reversible enzyme inhibition, coupled with a short pharmacokinetic half-life. This reduces dosing frequency, decreases body drug exposure and minimizes the dependence of drug action on the individual variations of drug metabolism commonly found in the elderly. In collaboration with Axonyx Corp. (New York, NY), three clinical trials have thus far been completed to evaluate the safety, maximum tolerated dose (MTD), pharmacokinetic (PK), pharmacodynamic (PD) and efficacy profile of phenserine, in healthy elderly and AD subjects. In blinded, placebo controlled studies, phenserine was well tolerated as a single oral dose of up to 10 mg once or twice daily. In a preliminary 12 week efficacy trial, phenserine 10 mg (BID) possessed a favorable safety profile and improved specific cognitive tasks in volunteers with mild to moderate AD. Its clinical development and evaluation continues. 1.1B. BChE: In normal brain, some 80% of cholinesterase activity is in the form of AChE and 20% is BChE. AChE activity is concentrated mainly in neurons, while BChE is primarily associated with glial cells. Kinetic evidence indicates a role for BChE, in hydrolysing excess ACh. In advanced AD, however, AChE activity decreases to 15% of normal levels in specific brain regions, whereas BChE activity increases. The normal ratio of BChE to AChE becomes mismatched in AD causing excess metabolism of already depleted levels of ACh. The first available reversible and highly potent BChE inhibitors have been synthesized and are in preclinical assessment to evaluate their potential as AD drug candidates. On going studies are focusing on cognition and the molecular mechanisms underpinning AD. 1.2. Molecular events associated with AD: The reduction in levels of the potentially toxic amyloid-beta peptide (Ab) has emerged as an important therapeutic goal in AD. Key targets for this goal are factors that affect the expression and processing of the Ab precursor protein (bAPP). Our studies show that phenserine, reduces bAPP and Ab levels in vivo and in tissue culture without toxicity. This activity is unrelated to its action as an anticholinesterase, but is post-transcriptional as it suppresses bAPP protein expression without altering bAPP mRNA levels. This is mediated via the 5' untranslated region (5 UTR) of bAPP mRNA. We have synthesized novel agents to both characterize the target and to selectively and optimally regulate bAPP mRNA translation to reduce Ab synthesis. Preclinical evaluation studies together with further medicinal chemistry is ongoing. 2. Stroke and Parkinson's disease: Drugs currently used in patients with stroke and Parkinson's disease (PD) provide temporary relief of symptoms, but do not prevent the cell death. Our target for drug development is the transcription factor, p53, as its up-regulation has been described as a common feature of several neurodegenerative disorders, and it is a pivotal step in the biochemical cascade that leads to apoptosis. We recently designed and synthesized a novel series of 2-imino-2,3,4,5,6,7-hexahydrobenzothiazole and 2-imino-2,3,4,5,6,7-hexahydrobenzoxazole analogues that inhibit p53 activity. Compounds are currently being assessed for neuroprotective action in tissue culture and in animal models (in collaboration with Dr. Mark Mattson, Laboratory of Neurosciences, NIA) to select agents of potential for evaluation as drug candidates. 3. Diabetes: Type 2 diabetes is a prevalent disease in the elderly, caused by a relative deficiency of insulin and a decrease in insulin action at insulin-sensitive tissues. Present treatments are unsatisfactory. In collaborative studies with Josephine Egan, M.D. (Diabetes Section, LCS, NIA), we have developed long acting and potent analogues of the endogenous peptide, GLP-1, as a potential treatment for diabetes. GLP-1 is secreted from the gut in response to food and is a potent secretagogue (i.e., it is insulinotropic). When given continuously to diabetic subjects or rodents, pharmacological concentrations of GLP-1 maintain blood glucose levels within their normal range. However, its rapid metabolism in humans and rodents limits its potential therapeutic value. Using GLP-1 as a starting point, numerous longer acting peptides were developed and assessed in animal models of diabetes. This research culminated in the development of the peptide, exendin-4 (Ex-4), into clinical studies in type 2 diabetes. Ex-4 is an endogenous peptide from the Gila monster lizard that shares 53% homology with GLP-1 and that potently binds and activate the GLP-1 receptor. Novel, chimeric peptides that combine the best features of GLP-1 and Ex-4 have been designed, synthesized and are under preclinical assessment in a variety of in vitro and in vivo diabetes models. Our recent studies have focused on the role of the GLP-1 receptor in the central and peripheral nervous systems. GLP-1, Ex-4 and specific analogues possess potent neurotrophic properties, and protect neuronal cells from oxidative and Ab-induced cell death. Neuroprotection in tissue culture translated to in vivo studies in a classical rodent cholinergic forebrain lesion model. Current studies are focused on the potential value of specific peptides in the treatment of peripheral neuropathies, such as the one that often accompanies type 2 diabetes. 4. New targets: Classic medicinal chemistry is being undertaken in the development of novel and potent inhibitors of a pharmacophore that reduces TNF-alpha synthesis by post-transcriptional mechanisms; specifically via translational regulation at its 3' UTR. Reductions in the cytokine, TNF-alpha, hold potential in the treatment of AD and a wide variety of auto-immune diseases. Potent agents have been synthesized and assessed in tissue culture studies. Future studies will assesses whether or not potency is translated into in vivo activity and efficacy in classical animal models.

药物和药理学探针的设计和开发：药物设计和开发部门的目标是开发针对与衰老相关的疾病病理生理学中涉及的关键步骤的新型药物，特别关注神经系统疾病，如阿尔茨海默病（AD）和中风，以及全身疾病，如糖尿病。