Parkinson's Disease: Advances in Treatment and the Syntheses of Various Classes of Pharmaceutical Drug Substances.

An overview of Parkinson's disease (PD) prevalence, diagnosis, and currently available treatment options is provided. A comprehensive list of different classes of marketed pharmaceutical drug products and the syntheses of various drug substances are summarized based on published literature.

General Synthesis of N-Alkylindoles from N,N-Dialkylanilines via [4 + 1] Annulative Double C-H Functionalization.

Strategies enabling the construction of indoles and novel polycyclic heterocycles from simple building blocks streamline syntheses in synthetic and medicinal chemistry. Herein, we report a C-H functionalization approach to N-alkylindoles proceeding via a double, site-selective C(sp3)-H/C(sp2)-H [4 + 1] annulation of readily accessed N,N-dialkylanilines. This protocol features a site-selective hydrogen atom transfer by a tuned N-tBu amidyl radical and addition of a sulfonyl diazo coupling partner, which promotes highly site-selective homolytic aromatic substitution of the (hetero)aromatic core. Mild decarboxylation of the annulation product enables the overall introduction of a carbyne equivalent into the N,N-dialkylaniline scaffold. Furthermore, the site-selectivity and mild conditions of the indolization facilitate direct access to N-alkyl indole scaffolds in late-stage functionalization (LSF) settings.

On-DNA Hydroalkylation to Introduce Diverse Bicyclo[1.1.1]pentanes and Abundant Alkyls via Halogen Atom Transfer.

DNA-encoded libraries have proven their tremendous value in the identification of new lead compounds for drug discovery. To access libraries in new chemical space, many methods have emerged to transpose traditional mol-scale reactivity to nmol-scale, on-DNA chemistry. However, procedures to access libraries with a greater fraction of C(sp3) content are still limited, and the need to "escape from flatland" more readily on-DNA remains. Herein, we report a Giese addition to install highly functionalized bicyclo[1.1.1]pentanes (BCPs) using tricyclo[1.1.1.01,3]pentane (TCP) as a radical linchpin, as well as other diverse alkyl groups, on-DNA from the corresponding organohalides as non-stabilized radical precursors. Telescoped procedures allow extension of the substrate pool by at least an order of magnitude to ubiquitous alcohols and carboxylic acids, allowing us to "upcycle" these abundant feedstocks to afford non-traditional libraries with different physicochemical properties for the small-molecule products (i.e., non-peptide libraries with acids). This approach is amenable to library production, as a DNA damage assessment revealed good PCR amplifiability and only 6% mutated sequences for a full-length DNA tag.

Foslevodopa/Foscarbidopa: A New Subcutaneous Treatment for Parkinson's Disease.

OBJECTIVE: The aim was to demonstrate that continuous s.c. infusion of a soluble levodopa (LD)/carbidopa (CD) phosphate prodrug combination effectively delivers stable LD exposure via a minimally invasive and convenient mode and has the potential to treat Parkinson's disease (PD) patients who are not well controlled on oral medication. METHODS: Foslevodopa and foscarbidopa were prepared and the equilibrium solubility and chemical stability examined in aqueous media with different values of pH. Solutions of foslevodopa/foscarbidopa (ratios ranging from 4:1 to 20:1) were prepared by dissolving pH-adjusted lyophilized materials in water and infused s.c. in healthy volunteers for ≤72 hours. Frequent blood samples were collected to measure LD and CD exposure, and safety was monitored throughout the study. RESULTS: Foslevodopa/foscarbidopa (ABBV-951) demonstrates high water solubility and excellent chemical stability near physiological pH, enabling continuous s.c. infusion therapy. After s.c. infusion, a stable LD pharmacokinetic (PK) profile was maintained for ≤72 hours, and the infusion was well tolerated. INTERPRETATION: Preparation of foslevodopa and foscarbidopa enables preclinical and clinical PK, safety, and tolerability studies in support of their advancement for the treatment of PD. In phase 1 clinical trials, foslevodopa/foscarbidopa demonstrates consistent and stable LD plasma exposure, supporting further studies of this treatment as a potentially transformational option for those suffering from PD. ANN NEUROL 2021;90:52-61.

Lithioarene Cycliacylation and Pd-Catalyzed Aminoethylation/Cyclization to Access Electronically Diverse Saturated Isoquinoline Derivatives.

We report operationally facile methods for the synthesis of substituted dihydroisoquinolinones and tetrahydroisoquinolines from readily accessible o-bromobenzyl bromides and o-bromobenzaldehydes, respectively. While classical electrophilic aromatic substitution reactions are tailored to the construction of saturated isoquinolines derived from electron-rich precursors, we demonstrate efficient syntheses from electronically diverse substrates to produce cyclized products as single regioisomers.

Scalable Asymmetric Syntheses of Foslevodopa and Foscarbidopa Drug Substances for the Treatment of Parkinson's Disease.

Foslevodopa (FLD, levodopa 4'-monophosphate, 3) and foscarbidopa (FCD, carbidopa 4'-monophosphate, 4) were identified as water-soluble prodrugs of levodopa (LD, 1) and carbidopa (CD, 2), respectively, which are useful for the treatment of Parkinson's disease. Herein, we describe asymmetric syntheses of FLD (3) and FCD (4) drug substances and their manufacture at pilot scale. The synthesis of FLD (3) employs a Horner-Wadsworth-Emmons olefination reaction followed by enantioselective hydrogenation of the double bond as key steps to introduce the α-amino acid moiety with the desired stereochemistry. The synthesis of FCD (4) features a Mizoroki-Heck reaction followed by enantioselective hydrazination to install the quaternary chiral center bearing a hydrazine moiety.

General Asymmetric Synthesis of Densely Functionalized Pyrrolidines via Endo-Selective [3+2] Cycloaddition of ß-Quaternary-Substituted Nitroalkenes and Azomethine Ylides.

A scalable endo-selective synthesis of 2,3,4,5-tetrasubstituted pyrrolidines via cycloaddition of nitroalkenes and azomethine ylides is reported using a P,N-type ferrocenyl ligand and [Cu(OTf)]2·C6H6. The robust method is tolerant of a wide range of functionalities, including rarely reported quaternary nitroalkene substitution and heteroaromatic and hindered ortho-substituted arenes on the azomethine ylide. Subsequent transformations highlight the utility of the method in the synthesis of densely functionalized small molecules suitable for fragment-based drug discovery and the cystic fibrosis C2-corrector clinical candidate ABBV-3221.

Synthesis and evaluation of 2'-dihalo ribonucleotide prodrugs with activity against hepatitis C virus.

Hepatitis C virus (HCV) nucleoside inhibitors have been a key focus of nearly 2 decades of HCV drug research due to a high barrier to drug resistance and pan-genotypic activity profile provided by molecules in this drug class. Our investigations focused on several potent 2'-halogenated uridine-based HCV polymerase inhibitors, resulting in the discovery of novel 2'-deoxy-2'-dihalo-uridine analogs that are potent inhibitors in replicon assays for all genotypes. Further studies to improve in vivo performance of these nucleoside inhibitors identified aminoisobutyric acid ethyl ester (AIBEE) phosphoramidate prodrugs 18a and 18c, which provide high levels of the active triphosphate in dog liver. AIBEE prodrug 18c was compared with sofosbuvir (1) by co-dosing both compounds by oral administration in dog (5 mg/kg each) and measuring liver concentrations of the active triphosphate metabolite at both 4 and 24 h post dosing. In this study, 18c provided liver triphosphate concentrations that were 6-fold higher than sofosbuvir (1) at both biopsy time points, suggesting that 18c could be a highly effective agent for treating HCV infected patients in the clinic.

Synthesis of ABBV-168, a 2'-Bromouridine for the Treatment of Hepatitis C.

ABBV-168 is a dihalogenated nucleotide under investigation for the treatment of hepatitis C virus. Three synthetic routes aimed at achieving the stereoselective installation of the C2' gem-Br,F substitution and subsequent Vorbruggen glycosylation were explored to prepare the penultimate nucleoside intermediate. Development culminated in a route to ABBV-168 featuring a de novo chromatography-free furanose synthesis, protecting group-directed Vorbruggen glycosylation, and highly selective phosphoramidation to furnish the API.

Synthesis of 2,2,2,-Trichloroethyl Aryl- and Vinyldiazoacetates by Palladium-Catalyzed Cross-Coupling.

An efficient and convenient synthesis of 2,2,2-trichloroethyl (TCE) aryl- and vinyldiazoacetates was achieved by palladium-catalyzed cross-coupling reactions between TCE diazoacetates and aryl or vinyl iodides. The broad substrate scope allows for rapid and facile formation of TCE aryl- and vinyldiazoacetates, which recently have emerged as versatile reagents for rhodium-carbene chemistry.

Stereoselective Synthesis of a Dipyridyl Transient Receptor Potential Vanilloid-3 (TRPV3) Antagonist.

An efficient asymmetric synthesis of dipyridyl TRPV3 antagonist 1 is reported. The four-step route involves two C-C bond-forming steps, a highly diastereoselective alkene hydration, and asymmetric ketone hydrosilylation in 97% ee.

Diversifying chemical space of DNA-encoded libraries: synthesis of 2-oxa-1-azaspiro(bicyclo[3.2.0])heptanes on-DNA via visible light-mediated energy transfer catalysis.

Azaspiro[3.3]heptanes are valuable synthetic targets for drug discovery programs. The challenges associated with the preparation and diversification of this moiety as compared to other small, saturated rings have led to limited applications of compounds containing this spirocycle. In this regard, important advances in the field of synthetic photochemistry have exploited the biradical nature of the triplet excited state of 2-isoxazoline-3-carboxylates, engaging these species in intermolecular coupling reactions under visible light irradiation. As a continuation of our program preparing F(sp3)-rich, structurally complex molecules for DNA-encoded library technology (DELT) applications via photocatalysis, we disclose herein the incorporation of unique and densely functionalized 2-oxa-1-azabicyclo[3.2.0]heptanes via [2+2] cycloaddition energy transfer sensitization, providing access to an unexplored library of azaspiro compounds, many of which include additional synthetic handles important for further functionalization of the DNA-conjugated products and for library production.

Dearomative intermolecular [2 + 2] photocycloaddition for construction of C(sp3)-rich heterospirocycles on-DNA.

DNA-encoded library (DEL) screens have significantly impacted new lead compound identification efforts within drug discovery. An advantage of DELs compared to traditional screening methods is that an exponentially broader chemical space can be effectively screened using only nmol quantities of billions of DNA-tagged, drug-like molecules. The synthesis of DELs containing diverse, sp3-rich spirocycles, an important class of molecules in drug discovery, has not been previously reported. Herein, we demonstrate the synthesis of complex and novel spirocyclic cores via an on-DNA, visible light-mediated intermolecular [2 + 2] cycloaddition of olefins with heterocycles, including indoles, azaindoles, benzofurans, and coumarins. The DNA-tagged exo-methylenecyclobutane substrates were prepared from easily accessible alkyl iodides and styrene derivatives. Broad reactivity with many other DNA-conjugated alkene substrates was observed, including unactivated and activated alkenes, and the process is tolerant of various heterocycles. The cycloaddition was successfully scaled from 10 to 100 nmol without diminished yield, indicative of this reaction's suitability for DNA-encoded library production. Evaluation of DNA compatibility with the developed reaction in a mock-library format showed that the DNA barcode was maintained with high fidelity, with <1% mutated sequences and >99% amplifiable DNA from quantitative polymerase chain reaction (PCR) and next generation sequencing (NGS).

Pharmacology of modality-specific transient receptor potential vanilloid-1 antagonists that do not alter body temperature.

The transient receptor potential vanilloid-1 (TRPV1) channel is involved in the development and maintenance of pain and participates in the regulation of temperature. The channel is activated by diverse agents, including capsaicin, noxious heat (≥ 43°C), acidic pH (< 6), and endogenous lipids including N-arachidonoyl dopamine (NADA). Antagonists that block all modes of TRPV1 activation elicit hyperthermia. To identify efficacious TRPV1 antagonists that do not affect temperature antagonists representing multiple TRPV1 pharmacophores were evaluated at recombinant rat and human TRPV1 channels with Ca(2+) flux assays, and two classes of antagonists were identified based on their differential ability to inhibit acid activation. Although both classes of antagonists completely blocked capsaicin- and NADA-induced activation of TRPV1, select compounds only partially inhibited activation of the channel by protons. Electrophysiology and calcitonin gene-related peptide release studies confirmed the differential pharmacology of these antagonists at native TRPV1 channels in the rat. Comparison of the in vitro pharmacological properties of these TRPV1 antagonists with their in vivo effects on core body temperature confirms and expands earlier observations that acid-sparing TRPV1 antagonists do not significantly increase core body temperature. Although both classes of compounds elicit equivalent analgesia in a rat model of knee joint pain, the acid-sparing antagonist tested is not effective in a mouse model of bone cancer pain.

Enabling Asymmetric Synthesis of ABBV-3748, a Corrector Compound for the Treatment of Cystic Fibrosis.

ABBV-3748 is a C2 corrector for the treatment of cystic fibrosis profiled among AbbVie's CFTR portfolio. A decagram-scale enabling asymmetric synthesis is described which addresses numerous shortcomings of the original route. Highlights include an InBr3-catalyzed intramolecular hydroarylation reaction that rapidly assembles the chromane core, an exceptionally efficient asymmetric hydrogenation of a primary enamide, and identification of tBuMgCl as a uniquely effective base in a challenging acyl sulfonamide formation.

Synthesis of A-9758, an Inverse Agonist of Retinoic Acid-Related Orphan Receptor γt.

A-9758 is an inverse agonist of retinoic acid-related orphan receptor γt with well-characterized in vitro and in vivo anti-inflammatory activity. A chromatography-free decagram-scale synthesis of this compound was developed to support pre-clinical research activities. This route was designed to enable late-stage structure-activity relationship studies of the amide moiety and convergently uses a reductive alkylation sequence between indole and benzaldehyde intermediates. A key advantage of this strategy is the fact that the indole precursor can be alkylated at C2, as required for A-9758, or at C3 to provide access to an isomeric chemical series. Access to the critical indole fragment was expedited via an underutilized SnAr/reductive cyclization cascade sequence, and the benzaldehyde fragment was prepared in two steps from inexpensive 2,4-dichlorobenzoic acid.

Fueling the Pipeline via Innovations in Organic Synthesis.

The paramount importance of synthetic organic chemistry in the pharmaceutical industry arises from the necessity to physically prepare all designed molecules to obtain key data to feed the design-synthesis-data cycle, with the medicinal chemist at the center of this cycle. Synthesis specialists accelerate the cycle of medicinal chemistry innovation by rapidly identifying and executing impactful synthetic methods and strategies to accomplish project goals, addressing the synthetic accessibility bottleneck that often plagues discovery efforts. At AbbVie, Discovery Synthesis Groups (DSGs) such as Centralized Organic Synthesis (COS) have been deployed as embedded members of medicinal chemistry teams, filling the gap between discovery and process chemistry. COS chemists provide synthetic tools, scaffolds, and lead compounds to fuel the pipeline. Examples of project contributions from neuroscience, cystic fibrosis, and virology illustrate the impact of the DSG approach. In the first ten years of innovative science in pursuit of excellence in synthesis, several advanced drug candidates, including ABBV-2222 (galicaftor) for cystic fibrosis and foslevodopa/foscarbidopa for Parkinson's disease, have emerged with key contributions from COS.

Asymmetric synthesis of pharmaceutically relevant 1-aryl-2-heteroaryl- and 1,2-diheteroarylcyclopropane-1-carboxylates.

This study describes general methods for the enantioselective syntheses of pharmaceutically relevant 1-aryl-2-heteroaryl- and 1,2-diheteroarylcyclopropane-1-carboxylates through dirhodium tetracarboxylate-catalysed asymmetric cyclopropanation of vinyl heterocycles with aryl- or heteroaryldiazoacetates. The reactions are highly diastereoselective and high asymmetric induction could be achieved using either (R)-pantolactone as a chiral auxiliary or chiral dirhodium tetracarboxylate catalysts. For meta- or para-substituted aryl- or heteroaryldiazoacetates the optimum catalyst was Rh2(R-p-Ph-TPCP)4. In the case of ortho-substituted aryl- or heteroaryldiazoacetates, the optimum catalyst was Rh2(R-TPPTTL)4. For a highly enantioselective reaction with the ortho-substituted substrates, 2-chloropyridine was required as an additive in the presence of either 4 Å molecular sieves or 1,1,1,3,3,3-hexafluoroisopropanol (HFIP). Under the optimized conditions, the cyclopropanation could be conducted in the presence of a variety of heterocycles, such as pyridines, pyrazines, quinolines, indoles, oxadiazoles, thiophenes and pyrazoles.

Desymmetrization of pibrentasvir for efficient prodrug synthesis.

A novel and practical desymmetrization tactic is described to access a new class of pibrentasvir prodrugs. The homotopic benzimidazoles of pibrentasvir (PIB) are differentiated via a one-pot di-Boc/mono-de-Boc selective N-Boc protection and formaldehyde adduct formation sequence, both enabled by crystallization-induced selectivity. The first step represents the only known application of the Horeau principle of statistical amplification for C 2-symmetric polyheterocycle regioselective functionalization. The resulting versatile intermediate is employed in the high-yielding preparation of several pibrentasvir prodrug candidates.

Synthesis of oxazolo[4,5-c]quinoline TRPV1 antagonists.

An efficient synthesis of 2-amino-oxazolo[4,5-c]quinoline TRPV1 antagonists is described via a thiourea formation/carbodiimide cyclization sequence. Synthetic route optimization eliminates intermediate isolations and facilitates the rapid preparation of a series of novel pentacyclic TRPV1 antagonists. From this series, compound (S)-4 was identified as a potent and selective ligand for the TRPV1 ion channel.