ABSTRACT
Genetic and pharmacological evidence indicates that the reduction of ataxia telangiectasia-mutated (ATM) kinase activity can ameliorate mutant huntingtin (mHTT) toxicity in cellular and animal models of Huntington's disease (HD), suggesting that selective inhibition of ATM could provide a novel clinical intervention to treat HD. Here, we describe the development and characterization of ATM inhibitor molecules to enable in vivo proof-of-concept studies in HD animal models. Starting from previously reported ATM inhibitors, we aimed with few modifications to increase brain exposure by decreasing P-glycoprotein liability while maintaining potency and selectivity. Here, we report brain-penetrant ATM inhibitors that have robust pharmacodynamic (PD) effects consistent with ATM kinase inhibition in the mouse brain and an understandable pharmacokinetic/PD (PK/PD) relationship. Compound 17 engages ATM kinase and shows robust dose-dependent inhibition of X-ray irradiation-induced KAP1 phosphorylation in the mouse brain. Furthermore, compound 17 protects against mHTT (Q73)-induced cytotoxicity in a cortical-striatal cell model of HD.
Subject(s)
Ataxia Telangiectasia Mutated Proteins/antagonists & inhibitors , Huntington Disease/drug therapy , Neuroprotective Agents/therapeutic use , ATP Binding Cassette Transporter, Subfamily B, Member 1/metabolism , Animals , Disease Models, Animal , Dogs , Humans , Madin Darby Canine Kidney Cells , Mice , Neuroprotective Agents/metabolism , Neuroprotective Agents/pharmacokinetics , Proof of Concept StudyABSTRACT
Synthesis of (S)-2-methyl-3-fluorophenyl cyclopentanone methyl ester (1S)-1 has been achieved by both inter- and intramolecular alkylation reactions on multigram scale, using chiral pool reagents. The intramolecular variant is a novel example of a chiral bis-electrophile reacting with a carbon nucleophile to form an enantiomerically pure all-carbon quaternary center.
ABSTRACT
Inhibition of class IIa histone deacetylase (HDAC) enzymes have been suggested as a therapeutic strategy for a number of diseases, including Huntington's disease. Catalytic-site small molecule inhibitors of the class IIa HDAC4, -5, -7, and -9 were developed. These trisubstituted diarylcyclopropanehydroxamic acids were designed to exploit a lower pocket that is characteristic for the class IIa HDACs, not present in other HDAC classes. Selected inhibitors were cocrystallized with the catalytic domain of human HDAC4. We describe the first HDAC4 catalytic domain crystal structure in a "closed-loop" form, which in our view represents the biologically relevant conformation. We have demonstrated that these molecules can differentiate class IIa HDACs from class I and class IIb subtypes. They exhibited pharmacokinetic properties that should enable the assessment of their therapeutic benefit in both peripheral and CNS disorders. These selective inhibitors provide a means for evaluating potential efficacy in preclinical models in vivo.
Subject(s)
Drug Design , Histone Deacetylase Inhibitors/pharmacology , Histone Deacetylases/metabolism , Huntington Disease/drug therapy , Animals , Dose-Response Relationship, Drug , Histone Deacetylase Inhibitors/chemical synthesis , Histone Deacetylase Inhibitors/chemistry , Histone Deacetylase Inhibitors/pharmacokinetics , Histone Deacetylases/classification , Humans , Isoenzymes/antagonists & inhibitors , Isoenzymes/metabolism , Male , Mice , Mice, Inbred C57BL , Microsomes, Liver/chemistry , Microsomes, Liver/metabolism , Models, Molecular , Molecular Structure , Structure-Activity RelationshipABSTRACT
The rhodium catalysed conjugate addition of organometallics to activated alkenes is a powerful synthetic tool for establishing new carbon-carbon bonds often with high stereoselectivity. The introduction of a practical, efficient method for introducing functionalised aryl and alkenyl fragments with predictable stereocontrol has caught the attention of synthetic chemists and emerging examples are growing in number and complexity. In this tutorial review, we document notable advances in the application of rhodium catalysed conjugate addition processes within the context of synthesis of complex molecules and intermediates in drug discovery. The chosen examples illustrate important issues regarding scope, selectivity and reactivity that will help guide the selection of appropriate donor and acceptor to achieve the desired carbon-carbon bond construction when planning new synthetic routes.
ABSTRACT
The concise enantioselective synthesis of hermitamides A and B is presented utilising a rhodium catalysed conjugate addition reaction to introduce the side chain and chiral information in a single step via an alkenyltrifluoroborate salt.
Subject(s)
Amides/chemical synthesis , Borates/chemistry , Fluorine/chemistry , Indoles/chemical synthesis , Phenethylamines/chemical synthesis , Rhodium/chemistry , Amides/chemistry , Catalysis , Hydrolysis , Indoles/chemistry , Kinetics , Phenethylamines/chemistry , Stereoisomerism , Substrate SpecificityABSTRACT
Alpha-benzyl acrylates, which are conveniently prepared from the corresponding aldehydes, can be employed as substrates in a tandem rhodium-catalyzed conjugate addition-enantioselective protonation protocol to afford enantiomerically enriched alpha,alpha'-dibenzyl esters. The synergistic effect of enantiopure ligand and proton source was rapidly optimized with use of a microwave reactor.
