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1.
J Med Chem ; 66(21): 14912-14927, 2023 11 09.
Article in English | MEDLINE | ID: mdl-37861679

ABSTRACT

Genetic mutation of the leucine-rich repeat kinase 2 (LRRK2) protein has been associated with Parkinson's disease (PD), a disabling and progressive neurodegenerative disorder that is devoid of efficacious disease-modifying therapies. Herein, we describe the invention of an amidoisoquinoline (IQ)-derived LRRK2 inhibitor lead chemical series. Knowledge-, structure-, and property-based drug design in concert with rigorous application of in silico calculations and presynthesis predictions enabled the prioritization of molecules with favorable CNS "drug-like" physicochemical properties. This resulted in the discovery of compound 8, which was profiled extensively before human ether-a-go-go (hERG) ion channel inhibition halted its progression. Strategic reduction of lipophilicity and basicity resulted in attenuation of hERG ion channel inhibition while maintaining a favorable CNS efflux transporter profile. Further structure- and property-based optimizations resulted in the discovery of preclinical candidate MK-1468. This exquisitely selective LRRK2 inhibitor has a projected human dose of 48 mg BID and a preclinical safety profile that supported advancement toward GLP toxicology studies.


Subject(s)
Parkinson Disease , Humans , Leucine-Rich Repeat Serine-Threonine Protein Kinase-2 , Parkinson Disease/drug therapy , Parkinson Disease/metabolism , Protein Kinase Inhibitors/pharmacology , Protein Kinase Inhibitors/therapeutic use , Protein Kinase Inhibitors/chemistry , Brain/metabolism , Mutation , Ion Channels/metabolism
2.
J Med Chem ; 65(1): 838-856, 2022 01 13.
Article in English | MEDLINE | ID: mdl-34967623

ABSTRACT

The leucine-rich repeat kinase 2 (LRRK2) protein has been genetically and functionally linked to Parkinson's disease (PD), a disabling and progressive neurodegenerative disorder whose current therapies are limited in scope and efficacy. In this report, we describe a rigorous hit-to-lead optimization campaign supported by structural enablement, which culminated in the discovery of brain-penetrant, candidate-quality molecules as represented by compounds 22 and 24. These compounds exhibit remarkable selectivity against the kinome and offer good oral bioavailability and low projected human doses. Furthermore, they showcase the implementation of stereochemical design elements that serve to enable a potency- and selectivity-enhancing increase in polarity and hydrogen bond donor (HBD) count while maintaining a central nervous system-friendly profile typified by low levels of transporter-mediated efflux and encouraging brain penetration in preclinical models.


Subject(s)
Antiparkinson Agents/chemical synthesis , Antiparkinson Agents/pharmacology , Brain/metabolism , Leucine-Rich Repeat Serine-Threonine Protein Kinase-2/antagonists & inhibitors , Quinazolines/chemical synthesis , Quinazolines/pharmacology , Antiparkinson Agents/pharmacokinetics , Biological Availability , Drug Design , Humans , Models, Molecular , Protein Kinase Inhibitors/pharmacology , Quinazolines/pharmacokinetics , Structure-Activity Relationship
3.
J Am Chem Soc ; 140(12): 4213-4217, 2018 03 28.
Article in English | MEDLINE | ID: mdl-29522330

ABSTRACT

Synthetic transformations that functionalize unactivated aliphatic C-H bonds in an intermolecular fashion offer unique strategies for the synthesis and late-stage derivatization of complex molecules. Herein we report a general approach to the intermolecular functionalization of aliphatic C-H bonds using an acridinium photoredox catalyst and phosphate salt under blue LED irradiation. This strategy encompasses a range of valuable C-H transformations, including the direct conversions of a C-H bond to C-N, C-F, C-Br, C-Cl, C-S, and C-C bonds, in all cases using the alkane substrate as the limiting reagent. Detailed mechanistic studies are consistent with the intermediacy of a putative oxygen-centered radical as the hydrogen atom-abstracting species in these processes.


Subject(s)
Acridines/chemistry , Alkanes/chemistry , Azides/chemical synthesis , Azides/chemistry , Catalysis , Molecular Structure , Oxidation-Reduction , Photochemical Processes
4.
Angew Chem Int Ed Engl ; 56(49): 15644-15648, 2017 12 04.
Article in English | MEDLINE | ID: mdl-29063646

ABSTRACT

The direct catalytic C-H amination of arenes is a powerful synthetic strategy with useful applications in pharmaceuticals, agrochemicals, and materials chemistry. Despite the advances in catalytic C-H functionalization, the use of aliphatic amine coupling partners is limited. Described herein is the construction of C-N bonds, using primary amines, by direct C-H functionalization with an acridinium photoredox catalyst under an aerobic atmosphere. A wide variety of primary amines, including amino acids and more complex amines are competent coupling partners. Various electron-rich aromatics and heteroaromatics are useful scaffolds in this reaction, as are complex, biologically active arenes. We also describe the ability to functionalize arenes that are not oxidized by an acridinium catalyst, such as benzene and toluene, thus supporting a reactive amine cation radical intermediate.


Subject(s)
Acridines/chemistry , Amines/chemistry , Amination , Catalysis , Molecular Structure , Oxidation-Reduction , Photochemical Processes
5.
J Am Chem Soc ; 139(32): 11288-11299, 2017 08 16.
Article in English | MEDLINE | ID: mdl-28718642

ABSTRACT

Direct C-H functionalization of aromatic compounds is a useful synthetic strategy that has garnered much attention because of its application to pharmaceuticals, agrochemicals, and late-stage functionalization reactions on complex molecules. On the basis of previous methods disclosed by our lab, we sought to develop a predictive model for site selectivity and extend this aryl functionalization chemistry to a selected set of heteroaromatic systems commonly used in the pharmaceutical industry. Using electron density calculations, we were able to predict the site selectivity of direct C-H functionalization in a number of heterocycles and identify general trends observed across heterocycle classes.


Subject(s)
Alkenes/chemistry , Hydrocarbons, Aromatic/chemistry , Palladium/chemistry , Amination , Benzene Derivatives/chemistry , Carbon/chemistry , Catalysis , Heterocyclic Compounds/chemistry , Hydrogen/chemistry , Indazoles/chemistry , Models, Molecular , Oxidation-Reduction , Photochemical Processes , Pyridines/chemistry , Quinolines/chemistry
6.
Acc Chem Res ; 49(9): 1997-2006, 2016 09 20.
Article in English | MEDLINE | ID: mdl-27588818

ABSTRACT

The development of methods for anti-Markovnikov alkene hydrofunctionalization has been a focal point of catalysis research for several decades. The vast majority of work on the control of regioselectivity for this reaction class has hinged on transition metal catalyst activation of olefin substrates. While progress has been realized, there are significant limitations to this approach, and a general solution for catalysis of anti-Markovnikov hydrofunctionalization reactions of olefins does not presently exist. In the past several years, this research lab has focused on alkene activation by single electron oxidation using organic photoredox catalysts to facilitate anti-Markovnikov hydrofunctionalization. By accessing reactive cation radical intermediates, we have realized a truly general approach to anti-Markovnikov olefin hydrofunctionalization reactions. We have identified a dual organic catalyst system consisting of an acridinium photooxidant, first reported by Fukuzumi, and a redox-active hydrogen atom donor that accomplishes a wide range of hydrofunctionalization reactions with complete anti-Markovnikov regiocontrol. This method relies on single electron oxidation of the alkene to reverse its polarity and results in the opposite regioselectivity for hydrofunctionalization. In 2012, we disclosed the anti-Markovnikov hydroetherification of alkenols employing an acridinium photocatalyst and a hydrogen atom donor that proceeds via interwoven polar and radical steps. This general catalyst system has enabled several important reactions in this area, including anti-Markovnikov alkene hydroacetoxylation, hydrolactonization, hydroamination, and hydrotrifluoromethylation reactions. More recently, we have also delineated conditions for intermolecular anti-Markovnikov hydroamination reactions of alkenes using either triflamide or nitrogen-containing heteroaromatic compounds such as pyrazole, indazole, imidazole, and 1,2,3-triazole. Further development led to a method for the anti-Markovnikov addition of mineral acids to olefins using lutidinium halide salts as convenient reagents to deliver the mineral acids. Acids including HCl, HF, H3PO4, and MeSO3H all participate in the hydrofunctionalization reactions, even with alkenes that are highly prone to polymerization. A combination of transient and steady-state absorption spectroscopy tools were employed to observe alkene cation radicals and the resultant acridine radical, lending support for an electron transfer mechanism. The origin of the anti-Markovnikov selectivity in these reactions is likely the result of a reversible addition of the nucleophile to the alkene cation radical resulting in a greater population of the more stable radical. Loss of a proton followed by reaction of the radical intermediate with the hydrogen atom donor completes the transformations. Again, by means of transient absorption spectroscopy, oxidative turnover of the acridine radical was observed to complete the dual catalytic cycle mechanistic picture.


Subject(s)
Acridines/chemistry , Alkenes/chemistry , Acridines/radiation effects , Catalysis/radiation effects , Cations/chemistry , Cyclization , Free Radicals/chemistry , Hydrogen/chemistry , Isomerism , Models, Chemical , Molecular Structure , Oxidation-Reduction
7.
Science ; 349(6254): 1326-30, 2015 Sep 18.
Article in English | MEDLINE | ID: mdl-26383949

ABSTRACT

Over the past several decades, organometallic cross-coupling chemistry has developed into one of the most reliable approaches to assemble complex aromatic compounds from preoxidized starting materials. More recently, transition metal-catalyzed carbon-hydrogen activation has circumvented the need for preoxidized starting materials, but this approach is limited by a lack of practical amination protocols. Here, we present a blueprint for aromatic carbon-hydrogen functionalization via photoredox catalysis and describe the utility of this strategy for arene amination. An organic photoredox-based catalyst system, consisting of an acridinium photooxidant and a nitroxyl radical, promotes site-selective amination of a variety of simple and complex aromatics with heteroaromatic azoles of interest in pharmaceutical research. We also describe the atom-economical use of ammonia to form anilines, without the need for prefunctionalization of the aromatic component.

8.
Org Lett ; 16(3): 904-7, 2014 Feb 07.
Article in English | MEDLINE | ID: mdl-24476062

ABSTRACT

A general strategy for the conversion of [2.2.2]-diazabicyclic alkene structures to 2-pyridone aromatic heterocyclic products is reported. The reaction sequence starts from 2,5-diketopiperazine (DKP) derivatives, is compatible with both aromatic and aliphatic aldehyde components, and can intercept either intra- or intermolecular cycloaddition manifolds. Priming of one aza-bridging function in the intermediate [2.2.2]-DKP scaffold permits cycloreversion (microwave heating) and selective extrusion of cyanate derivatives leading to the formation of 2-pyridone structures. Progress toward the synthesis of louisianin A and B, antiproliferative 2-pyridone natural products, is also disclosed.

9.
Org Lett ; 14(10): 2458-61, 2012 May 18.
Article in English | MEDLINE | ID: mdl-22571782

ABSTRACT

A domino reaction sequence involving aldol condensation, alkene isomerization, and intramolecular hetero-Diels-Alder cycloaddition for the synthesis of [2.2.2]-diazabicyclic structures is reported. Excellent diastereofacial control during the cycloaddition is enforced with a removable chiral phenyl aminal diketopiperazine substituent. The reaction sequence rapidly generates molecular complexity and is competent with both enolizable and nonenolizable aldehyde substrates (nine examples total). Progress toward the synthesis of malbrancheamide B, a protypical member of the [2.2.2]-diazabicyclic natural product family, is also disclosed.


Subject(s)
Alkenes/chemistry , Biological Products/chemical synthesis , Bridged Bicyclo Compounds, Heterocyclic/chemistry , Indole Alkaloids/chemical synthesis , Aldehydes/chemistry , Biological Products/chemistry , Bridged Bicyclo Compounds, Heterocyclic/chemical synthesis , Cycloaddition Reaction , Indole Alkaloids/chemistry , Molecular Structure , Stereoisomerism
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