RESUMO
Dysregulation of IL17A drives numerous inflammatory and autoimmune disorders with inhibition of IL17A using antibodies proven as an effective treatment. Oral anti-IL17 therapies are an attractive alternative option, and several preclinical small molecule IL17 inhibitors have previously been described. Herein, we report the discovery of a novel class of small molecule IL17A inhibitors, identified via a DNA-encoded chemical library screen, and their subsequent optimization to provide in vivo efficacious inhibitors. These new protein-protein interaction (PPI) inhibitors bind in a previously undescribed mode in the IL17A protein with two copies binding symmetrically to the central cavities of the IL17A homodimer.
Assuntos
DNA , Descoberta de Drogas , Interleucina-17 , Bibliotecas de Moléculas Pequenas , Interleucina-17/metabolismo , Interleucina-17/antagonistas & inibidores , Bibliotecas de Moléculas Pequenas/química , Bibliotecas de Moléculas Pequenas/farmacologia , DNA/metabolismo , DNA/química , Humanos , Animais , Relação Estrutura-Atividade , Ligação Proteica , CamundongosRESUMO
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.
RESUMO
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.
Assuntos
Fibrose Cística , Benzodioxóis/farmacologia , Benzodioxóis/uso terapêutico , Fibrose Cística/tratamento farmacológico , Regulador de Condutância Transmembrana em Fibrose Cística , Humanos , Mutação , Sulfonamidas/uso terapêuticoRESUMO
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.
Assuntos
Paládio , Tetra-Hidroisoquinolinas , Catálise , Ciclização , IsoquinolinasRESUMO
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.
RESUMO
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.
RESUMO
A research program to discover solubilizing prodrugs of the HCV NS5A inhibitor pibrentasvir (PIB) identified phosphomethyl analog 2 and trimethyl-lock (TML) prodrug 9. The prodrug moiety is attached to a benzimidazole nitrogen atom via an oxymethyl linkage to allow for rapid and complete release of the drug for absorption following phosphate removal by intestinal alkaline phosphatase. These prodrugs have good hydrolytic stability properties and improved solubility compared to PIB, both in aqueous buffer (pH 7) and FESSIF (pH 5). TML prodrug 9 provided superior in vivo performance, delivering high plasma concentrations of PIB in PK studies conducted in mice, dogs, and monkeys. The improved dissolution properties of these phosphate prodrugs provide them the potential to simplify drug dosage forms for PIB-containing HCV therapy.
Assuntos
Antivirais/química , Benzimidazóis/química , Pró-Fármacos/química , Pirrolidinas/química , Proteínas não Estruturais Virais/antagonistas & inibidores , Animais , Antivirais/farmacocinética , Antivirais/farmacologia , Área Sob a Curva , Benzimidazóis/farmacocinética , Benzimidazóis/farmacologia , Cães , Camundongos , Pró-Fármacos/farmacologia , Pirrolidinas/farmacocinética , Pirrolidinas/farmacologia , SolubilidadeRESUMO
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.
RESUMO
An enabling preclinical synthetic route to cystic fibrosis candidate ABBV-2222 is described. Two stereoselective steps provide access to an aminochroman intermediate with excellent control, and a late-stage demethylation/difluoromethylation sequence provides efficient access to the target molecule.
Assuntos
Benzoatos/síntese química , Benzoatos/farmacologia , Benzopiranos/síntese química , Benzopiranos/farmacologia , Regulador de Condutância Transmembrana em Fibrose Cística/metabolismo , Fibrose Cística/tratamento farmacológico , Benzoatos/química , Benzoatos/uso terapêutico , Benzopiranos/química , Benzopiranos/uso terapêutico , Técnicas de Química Sintética , Fibrose Cística/metabolismo , Metilação , EstereoisomerismoRESUMO
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.
Assuntos
Antivirais/farmacologia , Hepacivirus/efeitos dos fármacos , Hepatite C/tratamento farmacológico , Nucleotídeos/farmacologia , Antivirais/síntese química , Antivirais/química , Humanos , Testes de Sensibilidade Microbiana , Conformação Molecular , Nucleotídeos/síntese química , Nucleotídeos/químicaRESUMO
The room temperature palladium-catalyzed cross-coupling of aromatic and heteroaromatic halides with Reformatsky reagents derived from 1-bromocyclopropanecarboxylates provides an exceptionally mild method for enolate α-arylation. The method is tolerant of a wide range of functionalities and dramatically shortens many of the existing routes to access widely used 1,1-disubstituted cyclopropanecarboxylate derivatives.
RESUMO
The pentacyclic core skeleton of the cortistatins has been prepared in a stereoselective fashion by strategic use of an alkoxide-directed metallacycle-mediated annulative cross-coupling. This metal-centered tandem reaction delivers a polyunsaturated hydrindane and establishes the C13 stereodefined quaternary center with high levels of stereocontrol. Subsequent regio- and stereoselective global hydroboration results in the realization of the DE-trans ring fusion and a tertiary alcohol at C8. Establishment of the ABC-tricyclic subunit was then accomplished through phenolic oxidation/trans-acetalization, chemoselective reduction, regioselective cleavage, and intramolecular alkylation at C5.
Assuntos
Neuropeptídeos/síntese química , Acetais/química , Alquilação , Ciclização , Indanos/química , Oxirredução , EstereoisomerismoRESUMO
This Perspective describes the discovery and development of silyl glyoxylates, a new family of conjunctive reagents for use in multicomponent coupling reactions. The selection of the nucleophilic and electrophilic components determines whether the silyl glyoxylate reagent will function as a synthetic equivalent to the dipolar glycolic acid synthon, the glyoxylate anion synthon, or the α-keto ester homoenolate synthon. The ability to select for any of these reaction modes has translated to excellent structural diversity in the derived three- and four-component coupling adducts. Preliminary findings on the development of catalytic reactions using these reagents are detailed, as are the design and discovery of new reactions directed toward particular functional group arrays embedded within bioactive natural products.
Assuntos
Glioxilatos/química , Indicadores e Reagentes/química , Compostos de Organossilício/química , Catálise , Estrutura Molecular , EstereoisomerismoRESUMO
A convergent synthesis of highly substituted and stereodefined dihydroindanes is described from alkoxide-directed Ti-mediated cross-coupling of internal alkynes with substituted 4-hydroxy-1,6-enynes (substrates that derive from 2-directional functionalization of readily available epoxy alcohol derivatives). In addition to describing a new and highly stereoselective approach to bimolecular [2 + 2 + 2] annulation that delivers products not available with other methods in this area of chemical reactivity, evidence is provided to support annulation by way of regioselective alkyne-alkyne coupling, followed by metal-centered [4 + 2] rather than stepwise alkene insertion and reductive elimination. Overall, the reaction proceeds with exquisite stereochemical control and defines a convenient, convergent, and enantiospecific entry to fused carbocycles of great potential value in target-oriented synthesis and medicinal chemistry.
Assuntos
Indanos/síntese química , Compostos Organometálicos/química , Óxidos/química , Titânio/química , Alcinos/química , Ciclização , Indanos/química , Estrutura Molecular , EstereoisomerismoRESUMO
A formal synthesis of leustroducsin B has been completed. The synthesis relies upon a recently developed Reformatsky/Claisen condensation of silyl glyoxylates and enantioenriched ß-lactones that establishes two of the molecule's three core stereocenters and permits further elaboration to an intermediate in Imanishi's synthesis via reliable chemistry (Prasad reduction, asymmetric pentenylation, Mitsunobu inversion).
Assuntos
Glioxilatos/química , Compostos de Organossilício/química , Lactonas/síntese química , Lactonas/química , Estrutura Molecular , Compostos Organofosforados/síntese química , Compostos Organofosforados/química , PironasRESUMO
Reformatsky reagents react sequentially with silyl glyoxylates and ß-lactones to give highly functionalized Claisen condensation products. A heretofore undocumented instance of stereochemical 1,4-induction results in efficient transmission of ß-lactone stereochemistry to the emerging fully substituted stereocenter. Second-stage transformations reveal that the five heteroatom-containing functionalities embedded within the products are entirely chemo-differentiated, a circumstance that permits rapid assembly of the leustroducsin B core substructure.
Assuntos
Glioxilatos/química , Lactonas/química , Silanos/química , Acilação , Compostos Organofosforados/química , Pironas , EstereoisomerismoRESUMO
Three contiguous stereocenters can be established with remarkable diastereoselectivity in a double Reformatsky sequence. Densely functionalized gamma-butyrolactones were assembled rapidly by this approach, in which a ketone is used as the terminal electrophile (see scheme). Secondary transformations of the lactone products enhance their synthetic utility. R(1) = Me, H; R(2) = alkyl, aryl, CF(3); Bn = benzyl, TBS = tert-butyldimethylsilyl.
Assuntos
4-Butirolactona/síntese química , Glioxilatos/química , Cetonas/química , EstereoisomerismoRESUMO
Lanthanide triisopropoxides catalyze a rapid, tandem MPV reduction/Brook rearrangement/aldol sequence between silyl glyoxylates and aldehydes that achieves catalytic turnover through alkoxide transfer from a strain-release Lewis acidic silacycle.