RESUMO
Herein, we describe the design and synthesis of γ-secretase modulator (GSM) clinical candidate PF-06648671 (22) for the treatment of Alzheimer's disease. A key component of the design involved a 2,5-cis-tetrahydrofuran (THF) linker to impart conformational rigidity and lock the compound into a putative bioactive conformation. This effort was guided using a pharmacophore model since crystallographic information was not available for the membrane-bound γ-secretase protein complex at the time of this work. PF-06648671 achieved excellent alignment of whole cell in vitro potency (Aß42 IC50 = 9.8 nM) and absorption, distribution, metabolism, and excretion (ADME) parameters. This resulted in favorable in vivo pharmacokinetic (PK) profile in preclinical species, and PF-06648671 achieved a human PK profile suitable for once-a-day dosing. Furthermore, PF-06648671 was found to have favorable brain availability in rodent, which translated into excellent central exposure in human and robust reduction of amyloid ß (Aß) 42 in cerebrospinal fluid (CSF).
Assuntos
Doença de Alzheimer , Secretases da Proteína Precursora do Amiloide , Peptídeos beta-Amiloides , Secretases da Proteína Precursora do Amiloide/antagonistas & inibidores , Secretases da Proteína Precursora do Amiloide/metabolismo , Doença de Alzheimer/tratamento farmacológico , Humanos , Animais , Peptídeos beta-Amiloides/metabolismo , Ratos , Relação Estrutura-Atividade , Camundongos , Masculino , Descoberta de Drogas , Furanos/farmacologia , Furanos/farmacocinética , Furanos/síntese química , Furanos/química , Furanos/uso terapêutico , Ratos Sprague-Dawley , Encéfalo/metabolismoRESUMO
Herein, we disclose a new series of TYK2/ JAK1 inhibitors based upon a 3.1.0 azabicyclic substituted pyrimidine scaffold. We illustrate the use of structure-based drug design for the initial design and subsequent optimization of this series of compounds. One advanced example 19 met program objectives for potency, selectivity and ADME, and demonstrated oral activity in the adjuvant-induced arthritis rat model.
Assuntos
Artrite Experimental/tratamento farmacológico , Desenho de Fármacos , Janus Quinase 1/antagonistas & inibidores , Inibidores de Proteínas Quinases/farmacologia , TYK2 Quinase/antagonistas & inibidores , Animais , Artrite Experimental/metabolismo , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Feminino , Humanos , Janus Quinase 1/metabolismo , Estrutura Molecular , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/química , Ratos , Ratos Endogâmicos Lew , Relação Estrutura-Atividade , TYK2 Quinase/metabolismoRESUMO
Cytokine signaling is an important characteristic of autoimmune diseases. Many pro-inflammatory cytokines signal through the Janus kinase (JAK)/Signal transducer and activator of transcription (STAT) pathway. JAK1 is important for the γ-common chain cytokines, interleukin (IL)-6, and type-I interferon (IFN) family, while TYK2 in addition to type-I IFN signaling also plays a role in IL-23 and IL-12 signaling. Intervention with monoclonal antibodies (mAbs) or JAK1 inhibitors has demonstrated efficacy in Phase III psoriasis, psoriatic arthritis, inflammatory bowel disease, and rheumatoid arthritis studies, leading to multiple drug approvals. We hypothesized that a dual JAK1/TYK2 inhibitor will provide additional efficacy, while managing risk by optimizing selectivity against JAK2 driven hematopoietic changes. Our program began with a conformationally constrained piperazinyl-pyrimidine Type 1 ATP site inhibitor, subsequent work led to the discovery of PF-06700841 (compound 23), which is in Phase II clinical development (NCT02969018, NCT02958865, NCT03395184, and NCT02974868).
Assuntos
Antituberculosos/farmacologia , Artrite Experimental/prevenção & controle , Janus Quinase 1/antagonistas & inibidores , Mycobacterium tuberculosis/efeitos dos fármacos , Inibidores de Proteínas Quinases/farmacologia , Pirazóis/farmacologia , Pirimidinas/farmacologia , TYK2 Quinase/antagonistas & inibidores , Tuberculose/complicações , Animais , Artrite Experimental/induzido quimicamente , Artrite Experimental/microbiologia , Feminino , Estrutura Molecular , Ratos , Ratos Endogâmicos Lew , Tuberculose/microbiologiaRESUMO
Selective activation of dopamine D1 receptors (D1Rs) has been pursued for 40 years as a therapeutic strategy for neurologic and psychiatric diseases due to the fundamental role of D1Rs in motor function, reward processing, and cognition. All known D1R-selective agonists are catechols, which are rapidly metabolized and desensitize the D1R after prolonged exposure, reducing agonist response. As such, drug-like selective D1R agonists have remained elusive. Here we report a novel series of selective, potent non-catechol D1R agonists with promising in vivo pharmacokinetic properties. These ligands stimulate adenylyl cyclase signaling and are efficacious in a rodent model of Parkinson's disease after oral administration. They exhibit distinct binding to the D1R orthosteric site and a novel functional profile including minimal receptor desensitization, reduced recruitment of ß-arrestin, and sustained in vivo efficacy. These results reveal a novel class of D1 agonists with favorable drug-like properties, and define the molecular basis for catechol-specific recruitment of ß-arrestin to D1Rs.
Assuntos
Membrana Celular/efeitos dos fármacos , Agonistas de Dopamina/farmacologia , Receptores de Dopamina D1/agonistas , beta-Arrestinas/metabolismo , Animais , Células CHO , Linhagem Celular , Linhagem Celular Tumoral , Membrana Celular/metabolismo , Cricetinae , Cricetulus , Agonistas de Dopamina/química , Agonistas de Dopamina/metabolismo , Células HEK293 , Humanos , Microscopia de Fluorescência , Estrutura Molecular , Mutação , Ensaio Radioligante/métodos , Receptores de Dopamina D1/genética , Receptores de Dopamina D1/metabolismoRESUMO
The most common mutation in cystic fibrosis (CF) patients is deletion of F508 (ΔF508) in the first nucleotide binding domain (NBD1) of the CF transmembrane conductance regulator (CFTR). ΔF508 causes a decrease in the trafficking of CFTR to the cell surface and reduces the thermal stability of isolated NBD1; it is well established that both of these effects can be rescued by additional revertant mutations in NBD1. The current paradigm in CF small molecule drug discovery is that, like revertant mutations, a path may exist to ΔF508 CFTR correction through a small molecule chaperone binding to NBD1. We, therefore, set out to find small molecule binders of NBD1 and test whether it is possible to develop these molecules into potent binders that increase CFTR trafficking in CF-patient-derived human bronchial epithelial cells. Several fragments were identified that bind NBD1 at either the CFFT-001 site or the BIA site. However, repeated attempts to improve the affinity of these fragments resulted in only modest gains. Although these results cannot prove that there is no possibility of finding a high-affinity small molecule binder of NBD1, they are discouraging and lead us to hypothesize that the nature of these two binding sites, and isolated NBD1 itself, may not contain the features needed to build high-affinity interactions. Future work in this area may, therefore, require constructs including other domains of CFTR in addition to NBD1, if high-affinity small molecule binding is to be achieved.
Assuntos
Regulador de Condutância Transmembrana em Fibrose Cística/genética , Regulador de Condutância Transmembrana em Fibrose Cística/metabolismo , Fibrose Cística/genética , Descoberta de Drogas , Bibliotecas de Moléculas Pequenas/farmacologia , Sítios de Ligação , Cristalografia por Raios X , Fibrose Cística/tratamento farmacológico , Fibrose Cística/metabolismo , Regulador de Condutância Transmembrana em Fibrose Cística/química , Humanos , Simulação de Acoplamento Molecular , Ligação Proteica , Estrutura Terciária de Proteína , Deleção de Sequência , Bibliotecas de Moléculas Pequenas/químicaRESUMO
Herein we describe design strategies that led to the discovery of novel pyridopyrazine-1,6-dione γ-secretase modulators (GSMs) incorporating an indole motif as a heterocyclic replacement for a naphthyl moiety that was present in the original lead 9. Tactics involving parallel medicinal chemistry and in situ monomer synthesis to prepare focused libraries are discussed. Optimized indole GSM 29 exhibited good alignment of in vitro potency and physicochemical properties, and moderate reduction of brain Aß42 was achieved in a rat efficacy model when dosed orally at 30mg/kg. Labeling experiments using a clickable, indole-derived GSM photoaffinity probe demonstrated that this series binds to the presenilin N-terminal fragment (PS1-NTF) of the γ-secretase complex.
Assuntos
Secretases da Proteína Precursora do Amiloide/efeitos dos fármacos , Descoberta de Drogas , Indóis/farmacologia , Presenilinas/efeitos dos fármacos , Pirazinas/química , Animais , Indóis/química , RatosRESUMO
ß-Secretase 1 (BACE-1) is an attractive therapeutic target for the treatment and prevention of Alzheimer's disease (AD). Herein, we describe the discovery of a novel class of BACE-1 inhibitors represented by sulfamide 14g, using a medicinal chemistry strategy to optimize central nervous system (CNS) penetration by minimizing hydrogen bond donors (HBDs) and reducing P-glycoprotein (P-gp) mediated efflux. We have also taken advantage of the combination of structure based drug design (SBDD) to guide the optimization of the sulfamide analogues and the in silico tool WaterMap to explain the observed SAR. Compound 14g is a potent inhibitor of BACE-1 with excellent permeability and a moderate P-gp liability. Administration of 14g to mice produced a significant, dose-dependent reduction in central Aß(X-40) levels at a free drug exposure equivalent to the whole cell IC(50) (100 nM). Furthermore, studies of the P-gp knockout mouse provided evidence that efflux transporters affected the amount of Aß lowering versus that observed in wild-type (WT) mouse at an equivalent dose.
Assuntos
Doença de Alzheimer/tratamento farmacológico , Secretases da Proteína Precursora do Amiloide/antagonistas & inibidores , Ácido Aspártico Endopeptidases/antagonistas & inibidores , Compostos Aza/síntese química , Encéfalo/metabolismo , Compostos de Espiro/síntese química , Sulfonamidas/síntese química , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/genética , Secretases da Proteína Precursora do Amiloide/química , Peptídeos beta-Amiloides/metabolismo , Animais , Ácido Aspártico Endopeptidases/química , Compostos Aza/farmacocinética , Compostos Aza/farmacologia , Cristalografia por Raios X , Cães , Desenho de Fármacos , Feminino , Humanos , Células Madin Darby de Rim Canino , Masculino , Camundongos , Camundongos Knockout , Microssomos Hepáticos/metabolismo , Modelos Moleculares , Estrutura Molecular , Permeabilidade , Compostos de Espiro/farmacocinética , Compostos de Espiro/farmacologia , Estereoisomerismo , Relação Estrutura-Atividade , Sulfonamidas/farmacocinética , Sulfonamidas/farmacologia , TransfecçãoRESUMO
The aspartyl protease ß-secretase, or BACE, has been demonstrated to be a key factor in the proteolytic formation of Aß-peptide, a major component of plaques in the brains of Alzheimer's disease (AD) patients, and inhibition of this enzyme has emerged as a major strategy for pharmacologic intervention in AD. An X-ray-based fragment screen of Pfizer's proprietary fragment collection has resulted in the identification of a novel BACE binder featuring spiropyrrolidine framework. Although exhibiting only weak inhibitory activity against the BACE enzyme, the small compound was verified by biophysical and NMR-based methods as a bona fide BACE inhibitor. Subsequent optimization of the lead compound, relying heavily on structure-based drug design and computational prediction of physiochemical properties, resulted in a nearly 1000-fold improvement in potency while maintaining ligand efficiency and properties predictive of good permeability and low P-gp liability.
Assuntos
Secretases da Proteína Precursora do Amiloide/antagonistas & inibidores , Ácido Aspártico Endopeptidases/antagonistas & inibidores , Pirrolidinas/química , Compostos de Espiro/química , Secretases da Proteína Precursora do Amiloide/química , Ácido Aspártico Endopeptidases/química , Cristalografia por Raios X , Desenho de Fármacos , Humanos , Indóis/síntese química , Indóis/química , Indóis/farmacologia , Modelos Moleculares , Estrutura Molecular , Pirrolidinas/síntese química , Pirrolidinas/farmacologia , Compostos de Espiro/síntese química , Compostos de Espiro/farmacologia , Estereoisomerismo , Relação Estrutura-AtividadeRESUMO
Replacement of the central, para-substituted fluorophenyl ring in the γ-secretase inhibitor 1 (BMS-708,163) with the bicyclo[1.1.1]pentane motif led to the discovery of compound 3, an equipotent enzyme inhibitor with significant improvements in passive permeability and aqueous solubility. The modified biopharmaceutical properties of 3 translated into excellent oral absorption characteristics (~4-fold ↑ C(max) and AUC values relative to 1) in a mouse model of γ-secretase inhibition. In addition, SAR studies into other fluorophenyl replacements indicate the intrinsic advantages of the bicyclo[1.1.1]pentane moiety over conventional phenyl ring replacements with respect to achieving an optimal balance of properties (e.g., γ-secretase inhibition, aqueous solubility/permeability, in vitro metabolic stability). Overall, this work enhances the scope of the [1.1.1]-bicycle beyond that of a mere "spacer" unit and presents a compelling case for its broader application as a phenyl group replacement in scenarios where the aromatic ring count impacts physicochemical parameters and overall drug-likeness.
Assuntos
Secretases da Proteína Precursora do Amiloide/antagonistas & inibidores , Compostos Bicíclicos com Pontes/síntese química , Oxidiazóis/síntese química , Pentanos/síntese química , Sulfonamidas/síntese química , Administração Oral , Animais , Disponibilidade Biológica , Encéfalo/metabolismo , Compostos Bicíclicos com Pontes/farmacocinética , Compostos Bicíclicos com Pontes/farmacologia , Linhagem Celular , Cães , Feminino , Humanos , Camundongos , Microssomos Hepáticos/metabolismo , Oxidiazóis/farmacocinética , Oxidiazóis/farmacologia , Pentanos/farmacocinética , Pentanos/farmacologia , Ratos , Estereoisomerismo , Relação Estrutura-Atividade , Sulfonamidas/farmacocinética , Sulfonamidas/farmacologia , Distribuição TecidualRESUMO
A metabolism-based approach toward the optimization of a series of N-arylsulfonamide-based γ-secretase inhibitors is reported. The lead cyclohexyl analogue 6 suffered from extensive oxidation on the cycloalkyl motif by cytochrome P450 3A4, translating into poor human liver microsomal stability. Knowledge of the metabolic pathways of 6 triggered a structure-activity relationship study aimed at lowering lipophilicity through the introduction of polarity. This effort led to several tetrahydropyran and tetrahydrofuran analogues, wherein the 3- and 4-substituted variants exhibited greater microsomal stability relative to their 2-substituted counterparts. Further reduction in lipophilicity led to the potent γ-secretase inhibitor and 3-substituted oxetane 1 with a reduced propensity toward oxidative metabolism, relative to its 2-substituted isomer. The slower rates of metabolism with 3-substituted cyclic ethers most likely originate from reductions in lipophilicity and/or unfavorable CYP active site interactions with the heteroatom. Preliminary animal pharmacology studies with a representative oxetane indicate that the series is generally capable of lowering Aß in vivo. As such, the study also illustrates the improvement in druglikeness of molecules through the use of the oxetane motif.
Assuntos
Secretases da Proteína Precursora do Amiloide/antagonistas & inibidores , Éteres Cíclicos/síntese química , Sulfonamidas/síntese química , Peptídeos beta-Amiloides/líquido cefalorraquidiano , Peptídeos beta-Amiloides/metabolismo , Animais , Encéfalo/metabolismo , Linhagem Celular , Cristalografia por Raios X , Cães , Desenho de Fármacos , Éteres Cíclicos/metabolismo , Éteres Cíclicos/farmacologia , Humanos , Técnicas In Vitro , Camundongos , Microssomos Hepáticos/metabolismo , Oxirredução , Receptores Notch/metabolismo , Estereoisomerismo , Relação Estrutura-Atividade , Sulfonamidas/metabolismo , Sulfonamidas/farmacologia , Distribuição TecidualRESUMO
Alzheimer's disease (AD) poses a serious public health threat to the United States. Disease-modifying drugs slowing AD progression are in urgent need, but they are still unavailable. According to the amyloid cascade hypothesis, inhibition of ß- or γ-secretase, key enzymes for the production of amyloid ß (Aß), may be viable mechanisms for the treatment of AD. For the discovery of γ-secretase inhibitors (GSIs), the APP-overexpressing Tg2576 mouse has been the preclinical model of choice, in part because of the ease of detection of Aß species in its brain, plasma, and cerebrospinal fluid (CSF). Some biological observations and practical considerations, however, argue against the use of the Tg2576 mouse. We reasoned that an animal model would be suitable for GSI discovery if the pharmacokinetic (PK)/pharmacodynamic (PD) relationship of a compound for Aß lowering in this model is predictive of that in human. In this study, we assessed whether the background 129/SVE strain is a suitable preclinical pharmacology model for identifying new GSIs by evaluating the translatability of the intrinsic PK/PD relationships for brain and CSF Aß across the Tg2576 and 129/SVE mouse and human. Using semimechanistically based PK/PD modeling, our analyses indicated that the intrinsic PK/PD relationship for brain Aßx-42 and CSF Aßx-40 in the 129/SVE mouse is indicative of that for human CSF Aß. This result, in conjunction with practical considerations, strongly suggests that the 129/SVE mouse is a suitable model for GSI discovery. Concurrently, the necessity and utilities of PK/PD modeling for rational interpretation of Aß data are established.
Assuntos
Alanina/análogos & derivados , Secretases da Proteína Precursora do Amiloide/antagonistas & inibidores , Peptídeos beta-Amiloides/metabolismo , Azepinas/farmacologia , Descoberta de Drogas , Inibidores Enzimáticos/farmacologia , Oxidiazóis/farmacologia , Sulfonamidas/farmacologia , Alanina/sangue , Alanina/farmacocinética , Alanina/farmacologia , Secretases da Proteína Precursora do Amiloide/metabolismo , Peptídeos beta-Amiloides/sangue , Precursor de Proteína beta-Amiloide/metabolismo , Animais , Azepinas/sangue , Azepinas/farmacocinética , Encéfalo/efeitos dos fármacos , Encéfalo/enzimologia , Avaliação Pré-Clínica de Medicamentos , Inibidores Enzimáticos/sangue , Inibidores Enzimáticos/farmacocinética , Humanos , Camundongos , Camundongos da Linhagem 129 , Camundongos Transgênicos , Modelos Animais , Oxidiazóis/sangue , Oxidiazóis/farmacocinética , Bibliotecas de Moléculas Pequenas , Sulfonamidas/sangue , Sulfonamidas/farmacocinéticaRESUMO
A novel series of mGluR2 positive allosteric modulators (PAMs), 1-[(1-methyl-1H-imidazol-2-yl)methyl]-4-phenylpiperidines, is herein disclosed. Structure-activity relationship studies led to potent, selective mGluR2 PAMs with excellent pharmacokinetic profiles. A representative lead compound (+)-17e demonstrated dose-dependent inhibition of methamphetamine-induced hyperactivity and mescaline-induced scratching in mice, providing support for potential efficacy in treating psychosis.
Assuntos
Antipsicóticos/síntese química , Compostos Bicíclicos Heterocíclicos com Pontes/síntese química , Imidazóis/síntese química , Piperidinas/síntese química , Receptores de Glutamato Metabotrópico/metabolismo , Regulação Alostérica , Animais , Antipsicóticos/farmacocinética , Antipsicóticos/farmacologia , Disponibilidade Biológica , Encéfalo/metabolismo , Compostos Bicíclicos Heterocíclicos com Pontes/farmacocinética , Compostos Bicíclicos Heterocíclicos com Pontes/farmacologia , Linhagem Celular , Cães , Humanos , Hipercinese/induzido quimicamente , Hipercinese/tratamento farmacológico , Imidazóis/farmacocinética , Imidazóis/farmacologia , Técnicas In Vitro , Metanfetamina , Camundongos , Microssomos Hepáticos/metabolismo , Modelos Moleculares , Piperidinas/farmacocinética , Piperidinas/farmacologia , Conformação Proteica , Ensaio Radioligante , Ratos , Estereoisomerismo , Relação Estrutura-AtividadeRESUMO
The discovery, synthesis and SAR of a novel series of 3-benzyl-1,3-oxazolidin-2-ones as positive allosteric modulators (PAMs) of mGluR2 is described. Expedient hit-to-lead work on a single HTS hit led to the identification of a ligand-efficient and structurally attractive series of mGluR2 PAMs. Human microsomal clearance and suboptimal physicochemical properties of the initial lead were improved to give potent, metabolically stable and orally available mGluR2 PAMs.
Assuntos
Carbamatos/química , Oxazolidinonas/síntese química , Receptores de Glutamato Metabotrópico/antagonistas & inibidores , Receptores de Glutamato Metabotrópico/química , Esquizofrenia/tratamento farmacológico , Administração Oral , Regulação Alostérica , Sítio Alostérico , Química Farmacêutica/métodos , Desenho de Fármacos , Humanos , Concentração Inibidora 50 , Ligantes , Microssomos/metabolismo , Modelos Químicos , Estrutura Molecular , Oxazolidinonas/químicaRESUMO
The synthesis and structure-activity relationship (SAR) of a novel series of 3-(imidazolyl methyl)-3-aza-bicyclo[3.1.0]hexan-6-yl)methyl ethers, derived from a high throughput screening (HTS), are described. Subsequent optimization led to identification of potent, metabolically stable and orally available mGluR2 positive allosteric modulators (PAMs).
Assuntos
Regulação Alostérica , Compostos Azabicíclicos/síntese química , Benzimidazóis/síntese química , Química Farmacêutica/métodos , Éteres/química , Receptores de Glutamato Metabotrópico/química , Administração Oral , Sítio Alostérico , Animais , Compostos Azabicíclicos/farmacologia , Benzimidazóis/farmacologia , Desenho de Fármacos , Avaliação Pré-Clínica de Medicamentos , Humanos , Microssomos/efeitos dos fármacos , Modelos Químicos , Ratos , Esquizofrenia/tratamento farmacológico , Relação Estrutura-AtividadeRESUMO
A program directed to the possible adaptation of ring closing metathesis to a total synthesis of vinigrol is described. With a convenient route to intermediates of general type 3 available from a prior investigation, several candidate substrates were prepared. These included the epoxy dienes 10 and 22, the diacetoxy triene 42, and the heavily functionalized cyclohexane 48. The central issue of this approach was to convey a maximum degree of conformational flexibility to these functionalized intermediates, such that the olefinic termini of the side chains could enter into intramolecular carbon-carbon bond formation. In no example was ring closure observed to operate. Instead, the strategically placed pi-bonds were seen to migrate internally to the chain in select examples. Although the pivotal transformations failed, the deployment of a number of useful stereo-controlled reactions has ultimately resulted in the preparation of heavily substituted cis-decalins.
Assuntos
Ciclo-Octanos/química , Diterpenos/síntese química , Ciclização , Diterpenos/química , Desenho de Fármacos , Estrutura Molecular , EstereoisomerismoRESUMO
Evaluated in the present investigation are possible synthetic approaches to vinigrol based on the involvement of lactone rings as tools for the conformational rigidification of functionalized cis-octalins. Emphasis was placed on the structural arrangements resident in 3 and 5. The first of these systems proved to be highly strained and inaccessible. Especially notable was the finding that hydroxy ketenes 14 and 21 could be isolated and shown not to be amenable to cyclization when heated. The stereo-controlled assembly of 5 was successfully accomplished through exploitation of a related synthetic pathway. However, neither this attractive intermediate nor its close relative 33 could be processed in a manner that delivered the vinigrol framework. Nonetheless, several features of the routes deployed offer the prospect of wider application in other contexts.
Assuntos
Hidrocarbonetos Aromáticos com Pontes/química , Diterpenos/síntese química , Lactonas/química , Ciclização , Diterpenos/química , Desenho de Fármacos , Estrutura Molecular , EstereoisomerismoRESUMO
Attempts have been made to gain access to the vinigrol structural framework by way of three routes. These include reductive transannular cyclization, adaptation of the Ramberg-Backlund rearrangement, and deployment of the lactam-sulfoxide ring contraction protocol. While the first of these options involves direct transannular C-C bond formation, the other two embody the concept of larger ring construction as a prelude to ring contraction. The initial installation of a sulfur atom involves prior thiacyclononane formation, a process believed to be potentially easier to accomplish. However, arrival at 13, 14, or 17 was not achieved. Installation of the heterocyclic ring contained in 31 proved to be equally problematic. Increased disassembly of the molecular structure as featured in dibromide 20 did allow for direct conversion to sulfone 22. This advanced building block proved not be conducive to in situ alpha-chlorination and extrusion of the sulfur atom.