Advances in Drug Development for Parkinson's Disease: Present Status

Abstract

The major hallmark of Parkinson's disease (PD) is the progressive loss of dopaminergic neurons in the substantia nigra pars compacta, leading to the characteristic motor symptoms of resting tremors, bradykinesia and rigidity. Research in the field of PD therapy has been partly successful in terms of developing symptomatic treatments, but it also experienced several failures with regard to developing disease-modifying therapies. According to the definition of the Committee to Identify Neuroprotective Agents for Parkinson's, neuroprotection would be any intervention that favorably influences the disease process or underlying pathogenesis to produce enduring benefits for patients. A development of effective neuroprotective therapies resulting in clinically meaningful results is hampered by several factors in all research stages. Novel solutions might be offered by an evaluation of new targets throughout clinical studies, therapies emerging from drug repositioning approaches, multitarget approaches and network pharmacology. Several promising randomized controlled trials are in progress, and the increased collaboration between pharmaceutical companies and basic and clinical researchers has the potential to bring us closer to developing an optimum pharmaceutical approach for the treatment of PD. The aim of the present review is to give an overview of the neuroprotective agents and their targets currently investigated for the treatment of PD in phase I-III clinical trials.

Metal Chelation Therapy and Parkinson’s Disease: A Critical Review on the Thermodynamics of Complex Formation between Relevant Metal Ions and Promising or Established Drugs

“…Keywords and boolean logics employed for this bibliographic search are given in the Supplementary Materials. Several reviews appeared in 2014 or later, reporting lists of anti-PD compounds [1,12,[105][106][107][108][109][110]. These reviews list mainly molecules in use, or which underwent in vivo, or clinical phase tests against PD; here, we also decided to consider compounds which have just been tested in vitro, or even only proposed, e.g., after an in silico approach, because it is likely that some of these will undergo further tests in the following years.…”

Old and new challenges in Parkinson's disease therapeutics

“…CEP-1347 has been described as an anti-apoptotic drug able to inhibit the mixed lineage kinases, which are activators of apoptotic pathways implicated in the pathogenesis of PD (Eggert et al, 2010). From the application point of view, this drug was found to enhance neuronal survival in a variety of pre-clinical models and also to be safe and well tolerated in PD (Harikrishna Reddy et al, 2014). Indeed, CEP-1347 did not alter the pharmacokinetics of L-DOPA in PD patients, when both you administered in combination (Parkinson Study, 2004).…”

Systemic QSAR and phenotypic virtual screening: chasing butterflies in drug discovery

“…For PD, for example, those compounds successfully evaluated in a clinical trial for neuroprotective action in PD in Phase II or higher are appropriate starting points. In this way, we grant that the selected compounds induce the desired phenotype (neuroprotection in PD) because the main goal of Phase II clinical trials is to evaluate the therapeutic efficacy of the candidate [57]. …”

“…We inspected the literature to locate a reliable source that could provide ligands fitting the selected disease and phenotype. Consequently, from the drug candidates reported in [57], we collected a set of 12 of those successfully evaluated in Phase II and Phase III clinical trials as neuroprotective agents in PD. This set constitutes the starting point of our proof-of-concept exercise.…”

“…Tables 1 and 2 provide information on the 12 drug candidates selected and the set of therapeutic targets associated with their mechanism of neuroprotective action, respectively. The corresponding molecular structure representations were used as provided in [57]. …”