Protein kinases are a growing drug target class in disorders in peripheral tissues, but the development of kinase-targeted therapies for central nervous system (CNS) diseases remains a challenge, largely owing to issues associated specifically with CNS drug discovery. However, several candidate therapeutics that target CNS protein kinases are now in various stages of preclinical and clinical development. We review candidate compounds and discuss selected CNS protein kinases that are emerging as important therapeutic targets. In addition, we analyse trends in small-molecule properties that correlate with key challenges in CNS drug discovery, such as blood-brain barrier penetrance and cytochrome P450-mediated metabolism, and discuss the potential of future approaches that will integrate molecular-fragment expansion with pharmacoinformatics to address these challenges.Protein kinases regulate diverse cellular functions through the orchestrated propagation and amplification of cellular stimuli into distinct biological responses through coordinated signal transduction cascades. With several hundred kinases encoded in the human genome, almost every signal transduction process is influenced by interconnected phosphorylation events. Deregulation of kinase activity has been implicated in various diseases, ranging from vascular disorders and inflammatory diseases to neurological disorders and cancer 1,2 . This has generated intense interest in the pursuit of protein kinases as drug targets.However, most kinase-targeted drugs and potential kinase targets that have been investigated are for non-central nervous system (CNS) disorders. CNS disease indications for kinasetargeted drugs seem to be lagging behind those for other disease areas, such as cancer (FIG. 1), and ~25% of publications related to CNS disorders are for CNS cancers. This pattern is also seen in pharmaceutical industry pipelines that are publicly disclosed. For example, Novartis, the manufacturer of the kinase inhibitor cancer therapeutics imatinib (Gleevec) and nilotinib (Tasigna), has various oncology candidates and CNS-targeted therapies in clinical development. Half of the oncology pipeline are kinase inhibitors, but none of the disclosed CNS candidates seems to target protein kinases. Nevertheless, there is increasing interest in the development of kinase-targeted therapeutics for CNS indications [3][4][5][6][7][8][9][10][11] , and the established success in other disease indications provides encouragement for the development of smallmolecule kinase modulators for CNS disorders. NIH Public Access Author ManuscriptNat Rev Drug Discov. Author manuscript; available in PMC 2010 February 19. Published in final edited form as:Nat Rev Drug Discov. 2009 November ; 8(11): 892-909. doi:10.1038/nrd2999. NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author ManuscriptThis Review focuses on the special challenge of targeting protein kinases for CNS disease indications. A recent review 2 provides an up-to-date overview of targeting protein kinases i...
Overproduction of nitric oxide by neuronal nitric oxide synthase (nNOS) has been linked to several neurodegenerative diseases. We have recently designed potent and isoform selective inhibitors of nNOS, but the lead compound contains several basic functional groups. A large number of charges and hydrogen bond donors can impede the ability of molecules to cross the blood brain barrier and thereby limit the effectiveness of potential neurological therapeutics. Replacement of secondary amines in our lead compound with neutral ether and amide groups was made to increase bioavailability and to determine if the potency and selectivity of the inhibitor would be impacted. An ether analogue has been identified that retains a similar potency and selectivity to that of the lead compound, and shows increased ability to penetrate the blood brain barrier.
ABSTRACT:CYP2D6 substrate status is a critical Go/No Go decision criteria in central nervous system (CNS) drug discovery efforts because the polymorphic nature of CYP2D6 can lead to variable patient safety and drug efficacy. In addition, CYP2D6 is disproportionately involved in the metabolism of CNS drugs compared with other drug classes. Therefore, identifying trends in small molecule properties of CNS-penetrant compounds that can help discriminate potential CYP2D6 substrates from nonsubstrates would allow additional prioritization in the synthesis and biological evaluation of new therapeutic candidates. We report here the conversion of the CNS drug minaprine from substrate to nonsubstrate, as well as the conversion of the related CNS drug minozac from nonsubstrate to substrate, through the use of analog synthesis and CYP2D6 enzyme kinetic analyses. No single molecular property strongly correlated with substrate status for this 3-amino-4-methyl-6-phenylpyridazine scaffold, although molecular volume and charge appeared to be indirectly related. A parsed database of CYP2D6 substrates across diverse chemical structures was assembled and analyzed for physical property trends correlating with substrate status. We found that a complex interplay of properties influenced CYP2D6 substrate status and that the particular chemical scaffold affects which properties are most prominent. The results also identified an unexpected issue in CNS drug discovery, in that some property trends correlative with CYP2D6 substrates overlap previously reported properties that correlate with CNS penetrance. These results suggest the need for a careful balance in the design and synthesis of new CNS therapeutic candidates to avoid CYP2D6 substrate status while maintaining CNS penetrance.The avoidance of CYP2D6-mediated drug metabolism represents an early project management criteria in drug development because of its potential for variable patient safety and drug efficacy arising from genetic polymorphisms and its involvement in the metabolism of many existing drugs (Kramer et al., 2007;Leeson and Springthorpe, 2007). An example of an unwanted, variable patient response resulting from CYP2D6 polymorphisms is the response to codeine, which requires CYP2D6 conversion to the active drug morphine. Patients with a "slow metabolizer" phenotype caused by altered CYP2D6 expression or function can experience reduced analgesic effects resulting from diminished morphine production. In contrast, mutations causing a "rapid metabolizer" phenotype increase toxicity risks as excessive levels of morphine can be produced (Kirchheiner et al., 2007). As a result of such variance, there is considerable interest in identifying features that make small molecules favorable CYP2D6 substrates to prioritize early discovery efforts toward compounds with a lower likelihood of CYP2D6 involvement.The prevailing model of favorable CYP2D6 substrates includes the presence of a basic, protonated nitrogen atom 5, 7, or 10 Å from the site of metabolism (de Groot et al., 1997), bu...
Several prodrug approaches were taken to mask amino groups in two potent and selective neuronal nitric oxide synthase (nNOS) inhibitors containing either a primary or secondary amino group to lower the charge and improve blood-brain barrier (BBB) penetration. The primary amine was masked as an azide and the secondary amine as an amide or carbamate. The azide was not reduced to the amine under a variety of in vitro and ex vivo conditions. Despite the decrease in charge of the amino group as an amide and as carbamates, BBB penetration did not increase. It appears that the use of azides as prodrugs for primary amines or amides and carbamates as prodrugs for secondary amines are not universally effective approaches for CNS applications.Keywords amine prodrug; neuronal nitric oxide synthase inhibitor; blood-brain barrier; organic azide
Neurodegenerative disorders are rapidly becoming one of the greatest unmet health needs. This annual workshop facilitates innovation and progress in neurodegenerative disease drug discovery by convening stakeholders from charitable foundations, government, academia and industry who introduce scientists to the drug development and approval process. New to the 2012 workshop were candid discussions about re-visiting the CNS therapeutic development process. The continuing challenge is partly due to the poor forecasting potential of models of CNS diseases, as well as the lack of reproducibility of published studies, and greater need to increase focus on pharmacodynamic end points. Significant discussion centered on how to improve discovery approaches using examples of recent successes in the field. For example, the idea of combining reductionist, single-target strategies with functional-approach logic was suggested by several speakers, and widely discussed in the workshop. The didactic aspects of the workshop highlighted underlying concepts, best practices and trends that have characterized successful campaigns. The technical and scientific guidance was complemented by discussions of practical ways to approach the major funding gaps required for translation of projects from basic science to clinical investigations. This workshop has evolved to serve a critical educational need, with a wide range of investigator participation.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.