RESUMO
The discovery and optimization of novel N-(3-(1,3-dioxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yloxy)phenyl)benzenesulfonamide GPR119 agonists is described. Modification of the pyridylphthalimide motif of the molecule with R(1)=-Me and R(2)=-(i)Pr substituents, incorporated with a 6-fluoro substitution on the central phenyl ring offered a potent and metabolically stable tool compound 22.
Assuntos
Descoberta de Drogas , Piridinas/farmacologia , Receptores Acoplados a Proteínas G/agonistas , Sulfonamidas/farmacologia , Animais , Relação Dose-Resposta a Droga , Humanos , Microssomos Hepáticos/química , Microssomos Hepáticos/metabolismo , Estrutura Molecular , Piridinas/química , Piridinas/metabolismo , Ratos , Relação Estrutura-Atividade , Sulfonamidas/química , Sulfonamidas/metabolismoRESUMO
We describe the discovery and optimization of 5-(2-((1-(phenylsulfonyl)-1,2,3,4-tetrahydroquinolin-7-yl)oxy)pyridin-4-yl)-1,2,4-oxadiazoles as novel agonists of GPR119. Previously described aniline 2 had suboptimal efficacy in signaling assays using cynomolgus monkey (cyno) GPR119 making evaluation of the target in preclinical models difficult. Replacement of the aniline ring with a tetrahydroquinoline ring constrained the rotation of the aniline C-N bond and gave compounds with increased efficacy on human and cyno receptors. Additional optimization led to the discovery of 10, which possesses higher free fraction in plasma and improved pharmacokinetic properties in rat and cyno compared to 2.
Assuntos
Descoberta de Drogas , Oxidiazóis/farmacologia , Quinolinas/farmacologia , Receptores Acoplados a Proteínas G/agonistas , Animais , Relação Dose-Resposta a Droga , Humanos , Macaca fascicularis , Estrutura Molecular , Oxidiazóis/síntese química , Oxidiazóis/química , Quinolinas/síntese química , Quinolinas/química , Ratos , Relação Estrutura-AtividadeRESUMO
Retinol-Binding Protein 4 (RBP4) is a plasma protein that transports retinol (vitamin A) from the liver to peripheral tissues. This Letter highlights our efforts in discovering the first, to our knowledge, non-retinoid small molecules that bind to RBP4 at the retinol site and reduce serum RBP4 levels in mice, by disrupting the interaction between RBP4 and transthyretin (TTR), a plasma protein that binds RBP4 and protects it from renal excretion. Potent compounds were discovered and optimized quickly from high-throughput screen (HTS) hits utilizing a structure-based approach. Inhibitor co-crystal X-ray structures revealed unique disruptions of RBP4-TTR interactions by our compounds through induced loop conformational changes instead of steric hindrance exemplified by fenretinide. When administered to mice, A1120, a representative compound in the series, showed concentration-dependent retinol and RBP4 lowering.
Assuntos
Descoberta de Drogas , Proteínas Plasmáticas de Ligação ao Retinol/antagonistas & inibidores , Bibliotecas de Moléculas Pequenas/farmacologia , Animais , Cristalografia por Raios X , Relação Dose-Resposta a Droga , Humanos , Ligantes , Masculino , Camundongos , Modelos Moleculares , Estrutura Molecular , Ratos , Proteínas Plasmáticas de Ligação ao Retinol/metabolismo , Bibliotecas de Moléculas Pequenas/síntese química , Bibliotecas de Moléculas Pequenas/química , Relação Estrutura-Atividade , Vitamina A/sangueRESUMO
We recently reported on the discovery of AMG 232, a potent and selective piperidinone inhibitor of the MDM2-p53 interaction. AMG 232 is being evaluated in human clinical trials for cancer. Continued exploration of the N-alkyl substituent of this series, in an effort to optimize interactions with the MDM2 glycine-58 shelf region, led to the discovery of sulfonamides such as compounds 31 and 38 that have similar potency, hepatocyte stability and rat pharmacokinetic properties to AMG 232.
Assuntos
Acetatos/farmacologia , Descoberta de Drogas , Piperidonas/farmacologia , Proteínas Proto-Oncogênicas c-mdm2/antagonistas & inibidores , Sulfonamidas/química , Proteína Supressora de Tumor p53/antagonistas & inibidores , Acetatos/química , Animais , Cristalografia por Raios X , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Modelos Moleculares , Conformação Molecular , Piperidonas/química , Ligação Proteica/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-mdm2/química , Ratos , Relação Estrutura-Atividade , Proteína Supressora de Tumor p53/químicaRESUMO
Fatty acid amide hydrolase (FAAH), an amidase-signature family member, is an integral membrane enzyme that degrades lipid amides including the endogenous cannabinoid anandamide and the sleep-inducing molecule oleamide. Both genetic knock out and pharmacological administration of FAAH inhibitors in rodent models result in analgesic, anxiolytic, and antiinflammatory phenotypes. Targeting FAAH activity, therefore, presents a promising new therapeutic strategy for the treatment of pain and other neurological-related or inflammatory disorders. Nearly all FAAH inhibitors known to date attain their binding potency through a reversible or irreversible covalent modification of the nucleophile Ser241 in the unusual Ser-Ser-Lys catalytic triad. Here, we report the discovery and mechanism of action of a series of ketobenzimidazoles as unique and potent noncovalent FAAH inhibitors. Compound 2, a representative of these ketobenzimidazoles, was designed from a series of ureas that were identified from high-throughput screening. While urea compound 1 is characterized as an irreversible covalent inhibitor, the cocrystal structure of FAAH complexed with compound 2 reveals that these ketobenzimidazoles, though containing a carbonyl moiety, do not covalently modify Ser241. These inhibitors achieve potent inhibition of FAAH activity primarily from shape complementarity to the active site and through numerous hydrophobic interactions. These noncovalent compounds exhibit excellent selectivity and good pharmacokinetic properties. The discovery of this distinctive class of inhibitors opens a new avenue for modulating FAAH activity through nonmechanism-based inhibition.
Assuntos
Amidoidrolases/antagonistas & inibidores , Benzimidazóis/isolamento & purificação , Benzimidazóis/metabolismo , Descoberta de Drogas/métodos , Inibidores Enzimáticos/isolamento & purificação , Inibidores Enzimáticos/metabolismo , Modelos Moleculares , Animais , Benzimidazóis/farmacocinética , Cumarínicos , Cristalização , Inibidores Enzimáticos/farmacocinética , Escherichia coli , Humanos , Estrutura Molecular , Ratos , Espectrofotometria Ultravioleta , Espectrometria de Massas em Tandem , Ureia/metabolismoRESUMO
We describe the discovery of a series of arylsulfonyl 3-(pyridin-2-yloxy)anilines as GPR119 agonists derived from compound 1. Replacement of the three methyl groups in 1 with metabolically stable moieties led to the identification of compound 34, a potent and efficacious GPR119 agonist with improved pharmacokinetic (PK) properties.
Assuntos
Compostos de Anilina/química , Compostos de Anilina/farmacologia , Receptores Acoplados a Proteínas G/agonistas , Compostos de Anilina/síntese química , Animais , Diabetes Mellitus Tipo 2/tratamento farmacológico , Descoberta de Drogas , Humanos , Camundongos , Modelos Moleculares , Receptores Acoplados a Proteínas G/química , Relação Estrutura-AtividadeRESUMO
Sphingosine-1-phosphate (S1P) signaling plays a vital role in mitogenesis, cell migration and angiogenesis. Sphingosine kinases (SphKs) catalyze a key step in sphingomyelin metabolism that leads to the production of S1P. There are two isoforms of SphK and observations made with SphK deficient mice show the two isoforms can compensate for each other's loss. Thus, inhibition of both isoforms is likely required to block SphK dependent angiogenesis. A structure based approach was used to design and synthesize a series of SphK inhibitors resulting in the identification of the first potent inhibitors of both isoforms of human SphK. Additionally, to our knowledge, this series of inhibitors contains the only sufficiently potent inhibitors of murine SphK1 with suitable physico-chemical properties to pharmacologically interrogate the role of SphK1 in rodent models and to reproduce the phenotype of SphK1 (-/-) mice.
Assuntos
Desenho de Fármacos , Inibidores Enzimáticos/síntese química , Fosfotransferases (Aceptor do Grupo Álcool)/antagonistas & inibidores , Fosfotransferases (Aceptor do Grupo Álcool)/química , Bibliotecas de Moléculas Pequenas/síntese química , Animais , Células Cultivadas , Cristalografia por Raios X , Ativação Enzimática/efeitos dos fármacos , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Humanos , Camundongos , Estrutura Molecular , Isoformas de Proteínas/química , Ratos , Bibliotecas de Moléculas Pequenas/química , Bibliotecas de Moléculas Pequenas/farmacologia , Relação Estrutura-AtividadeRESUMO
The present report describes our efforts to convert an existing LXR agonist into an LXR antagonist using a structure-based approach. A series of benzenesulfonamides was synthesized based on structural modification of a known LXR agonist and was determined to be potent dual liver X receptor (LXR α/ß) ligands. Herein we report the identification of compound 54 as the first reported LXR antagonist that is suitable for pharmacological in vivo evaluation in rodents.
Assuntos
Descoberta de Drogas , Receptores Nucleares Órfãos/antagonistas & inibidores , Sulfonamidas/farmacologia , Animais , Relação Dose-Resposta a Droga , Células HEK293 , Células Hep G2 , Humanos , Ligantes , Receptores X do Fígado , Masculino , Camundongos , Estrutura Molecular , Ratos , Ratos Sprague-Dawley , Relação Estrutura-Atividade , Sulfonamidas/síntese química , Sulfonamidas/química , BenzenossulfonamidasRESUMO
Two classes of ACK1 inhibitors, 4,5,6-trisubstituted furo[2,3-d]pyrimidin4-amines and 4,5,6-trisubstituted 7H-pyrrolo[2,3-d]pyrimidin-4-amines, were discovered and evaluated as ACK1 inhibitors. Further structural refinement led to the identification of potent and selective dithiolane inhibitor 37.
Assuntos
Furanos/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Proteínas Tirosina Quinases/antagonistas & inibidores , Pirimidinas/farmacologia , Pirróis/farmacologia , Relação Dose-Resposta a Droga , Furanos/síntese química , Furanos/química , Humanos , Modelos Moleculares , Estrutura Molecular , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/química , Proteínas Tirosina Quinases/metabolismo , Pirimidinas/síntese química , Pirimidinas/química , Pirróis/síntese química , Pirróis/química , Estereoisomerismo , Relação Estrutura-AtividadeRESUMO
Structural modification of a series of dual LXRα/ß agonists led to the identification of a new class of LXRß partial agonists. An X-ray co-crystal structure shows that a representative member of this series, pyrrole 5, binds to LXRß with a reversed orientation compared to 1.
Assuntos
Receptores Nucleares Órfãos/agonistas , Isoformas de Proteínas/agonistas , Pirróis/síntese química , Sítios de Ligação , Células CACO-2 , Cristalografia por Raios X , Genes Reporter , Células HEK293 , Humanos , Receptores X do Fígado , Receptores Nucleares Órfãos/química , Ligação Proteica , Isoformas de Proteínas/química , Pirróis/farmacologia , Relação Estrutura-Atividade , TransfecçãoRESUMO
We discovered novel pyrrolidine MCHR1 antagonist 1 possessing moderate potency. Profiling of pyrrolidine 1 demonstrated that it was an inhibitor of the hERG channel. Investigation of the structure-activity relationship of this class of pyrrolidines allowed us to optimize the MCHR1 potency and decrease the hERG inhibition. Increasing the acidity of the amide proton by converting the benzamide in lead 1 to an anilide provided single digit nanomolar MCHR1 antagonists while replacing the dimethoxyphenyl ring of 1 with alkyl groups possessing increased polarity dramatically reduced the hERG inhibition.
Assuntos
Canais de Potássio Éter-A-Go-Go/metabolismo , Pirrolidinas/química , Receptores de Somatostatina/antagonistas & inibidores , Canal de Potássio ERG1 , Canais de Potássio Éter-A-Go-Go/antagonistas & inibidores , Humanos , Pirrolidinas/síntese química , Pirrolidinas/farmacologia , Receptores de Somatostatina/metabolismo , Estereoisomerismo , Relação Estrutura-AtividadeRESUMO
Starting from a series of ureas that were determined to be mechanism-based inhibitors of FAAH, several spirocyclic ureas and lactams were designed and synthesized. These efforts identified a series of novel, noncovalent FAAH inhibitors with in vitro potency comparable to known covalent FAAH inhibitors. The mechanism of action for these compounds was determined through a combination of SAR and co-crystallography with rat FAAH.
Assuntos
Amidoidrolases/antagonistas & inibidores , Inibidores Enzimáticos/química , Amidoidrolases/metabolismo , Animais , Sítios de Ligação , Simulação por Computador , Cristalografia por Raios X , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/farmacocinética , Humanos , Lactamas/síntese química , Lactamas/química , Lactamas/farmacocinética , Ratos , Compostos de Espiro/química , Relação Estrutura-Atividade , Ureia/síntese química , Ureia/química , Ureia/farmacocinéticaRESUMO
Free fatty acid receptor 2 (FFA2) is a G-protein coupled receptor for which only short-chain fatty acids (SCFAs) have been reported as endogenous ligands. We describe the discovery and optimization of phenylacetamides as allosteric agonists of FFA2. These novel ligands can suppress adipocyte lipolysis in vitro and reduce plasma FFA levels in vivo, suggesting that these allosteric modulators can serve as pharmacological tools for exploring the potential function of FFA2 in various disease conditions.
Assuntos
Acetamidas/síntese química , Receptores de Superfície Celular/agonistas , Receptores Acoplados a Proteínas G/agonistas , Acetamidas/química , Acetamidas/farmacocinética , Regulação Alostérica , Animais , AMP Cíclico/metabolismo , Descoberta de Drogas , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Ratos , Receptores de Superfície Celular/metabolismo , Receptores Acoplados a Proteínas G/metabolismo , Relação Estrutura-AtividadeRESUMO
A new structural class of DGAT1 inhibitors was discovered and the structure-activity relationship was explored. The pyrrolotriazine core of the original lead molecule was changed to a pyrrolopyridazine core providing an increase in potency. Further exploration resulted in optimization of the propyl group at C7 and the discovery that the ester at C6 could be replaced by five-membered heterocyclic rings. The analogs prepared have DGAT1 IC(50) values ranging from >10 µM to 48 nM.
Assuntos
Diacilglicerol O-Aciltransferase/antagonistas & inibidores , Diacilglicerol O-Aciltransferase/metabolismo , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Piridazinas/química , Piridazinas/farmacologia , Pirróis/química , Pirróis/farmacologia , Linhagem Celular , Inibidores Enzimáticos/síntese química , Humanos , Concentração Inibidora 50 , Piridazinas/síntese química , Pirróis/síntese química , Esterol O-Aciltransferase/antagonistas & inibidores , Esterol O-Aciltransferase/metabolismo , Relação Estrutura-AtividadeRESUMO
STUDY OBJECTIVES: A major challenge in treating insomnia is to find effective medicines with fewer side effects. Activation of G-protein-gated inward rectifying K+ channels (GIRKs) by GABAB agonists baclofen or γ-hydroxybutyric acid (GHB) promotes nonrapid eye movement (NREM) sleep and consolidates sleep. However, baclofen has poor brain penetration, GHB possesses abuse liability, and in rodents both drugs cause spike-wave discharges (SWDs), an absence seizure activity. We tested the hypothesis that direct GIRK activation promotes sleep without inducing SWD using ML297, a potent and selective GIRK activator. METHODS: Whole-cell patch-clamp recordings from hypocretin/orexin or hippocampal neurons in mouse brain slices were made to study neuronal excitability and synaptic activity; spontaneous activity, locomotion, contextual and tone-conditioned memory, and novel object recognition were assessed. Electroencephalogram/electromyogram (EEG/EMG) recordings were used to study GIRK modulation of sleep. RESULTS: ML297, like baclofen, caused membrane hyperpolarization, decreased input resistance, and blockade of spontaneous action potentials. Unlike baclofen, ML297 (5-10 µM) did not cause significant depression of postsynaptic excitatory and inhibitory currents (EPSCs-IPSCs), indicating preferential postsynaptic inhibition. ML297 (30 mg/kg, i.p.) inhibited wake activity and locomotion, and preferentially increased NREM sleep without altering EEG delta power, REM sleep, inducing SWDs, or impairing conditioned memory and novel object recognition. CONCLUSIONS: This study finds that direct activation of neuronal GIRK channels modulates postsynaptic membrane excitability and prolongs NREM sleep without changing sleep intensity, inducing SWDs, or impairing memory in rodents. These results suggest that direct GIRK activation with a selective compound may present an innovative approach for the treatment of chronic insomnia.
Assuntos
Canais de Potássio Corretores do Fluxo de Internalização Acoplados a Proteínas G/agonistas , Canais de Potássio Corretores do Fluxo de Internalização Acoplados a Proteínas G/metabolismo , Compostos de Fenilureia/farmacologia , Pirazóis/farmacologia , Fases do Sono/fisiologia , Potenciais de Ação/efeitos dos fármacos , Potenciais de Ação/fisiologia , Animais , Eletromiografia/efeitos dos fármacos , Eletromiografia/métodos , Feminino , Hipocampo/efeitos dos fármacos , Hipocampo/fisiologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Neurônios/efeitos dos fármacos , Neurônios/fisiologia , Técnicas de Cultura de Órgãos , Técnicas de Patch-Clamp/métodos , Fases do Sono/efeitos dos fármacosRESUMO
Protein-protein interactions (PPIs) governing the recognition of substrates by E3 ubiquitin ligases are critical to cellular function. There is significant therapeutic potential in the development of small molecules that modulate these interactions; however, rational design of small molecule enhancers of PPIs remains elusive. Herein, we report the prospective identification and rational design of potent small molecules that enhance the interaction between an oncogenic transcription factor, ß-Catenin, and its cognate E3 ligase, SCFß-TrCP. These enhancers potentiate the ubiquitylation of mutant ß-Catenin by ß-TrCP in vitro and induce the degradation of an engineered mutant ß-Catenin in a cellular system. Distinct from PROTACs, these drug-like small molecules insert into a naturally occurring PPI interface, with contacts optimized for both the substrate and ligase within the same small molecule entity. The prospective discovery of 'molecular glue' presented here provides a paradigm for the development of small molecule degraders targeting hard-to-drug proteins.
Assuntos
Bibliotecas de Moléculas Pequenas/análise , Bibliotecas de Moléculas Pequenas/farmacologia , Ubiquitina-Proteína Ligases/metabolismo , Células HEK293 , Humanos , Fosforilação/efeitos dos fármacos , Ligação Proteica/efeitos dos fármacos , Proteólise/efeitos dos fármacos , Bibliotecas de Moléculas Pequenas/química , Especificidade por Substrato/efeitos dos fármacos , Ubiquitinação/efeitos dos fármacos , beta Catenina/metabolismo , Proteínas Contendo Repetições de beta-Transducina/metabolismoRESUMO
FFA2 (GPR43) has been identified as a receptor for short-chain fatty acids (SCFAs) that include acetate and propionate. FFA2 is highly expressed in islets, a subset of immune cells, and adipocytes. Although the potential roles of FFA2 activation in these tissues have previously been described, the physiological functions are still unclear. The potency for SCFAs on FFA2 is low, in the high micromolar to millimolar concentrations. To identify better pharmacological tools to study receptor function, we used high-throughput screening (HTS) to discover a series of small molecule phenylacetamides as novel and more potent FFA2 agonists. This series is specific for FFA2 over FFA1 (GPR40) and FFA3 (GPR41), and it is able to activate both the Galpha(q) and Galpha(i) pathways in vitro on Chinese hamster ovary cells stably expressing FFA2. Treatment of adipocytes with these compounds also resulted in Galpha(i)-dependent inhibition of lipolysis similar to that of endogenous ligands (SCFAs). It is noteworthy that these compounds not only acted as FFA2 agonists but also exhibited positive cooperativity with acetate or propionate. The observed allosteric modulation was consistent in all the functional assays that we have explored, including cAMP, calcium mobilization, guanosine 5'-[gamma-thio]triphosphate binding, and lipolysis. Molecular modeling analysis of FFA2 based on human beta(2)-adrenergic receptor structure revealed potential nonoverlapping binding sites for the endogenous and synthetic ligands, further providing insight into the binding pocket for the allosteric interactions. This is the first report describing the identification of novel allosteric modulators with agonist activity for FFA2, and these compounds may serve as tools for further unraveling the physiological functions of the receptor and its involvement in various diseases.
Assuntos
Benzenoacetamidas/farmacologia , Receptores de Superfície Celular/agonistas , Tiazóis/farmacologia , Células 3T3-L1 , Adipócitos/efeitos dos fármacos , Adipócitos/metabolismo , Regulação Alostérica , Sequência de Aminoácidos , Animais , Benzenoacetamidas/química , Células CHO , Cricetinae , Cricetulus , Humanos , Ligantes , Lipólise/efeitos dos fármacos , Camundongos , Modelos Moleculares , Dados de Sequência Molecular , Ensaio Radioligante , Relação Estrutura-Atividade , Tiazóis/químicaRESUMO
A new series of pyrazolo[3,4-d]pyrimidine-3,6-diamines was designed and synthesized as potent and selective inhibitors of the nonreceptor tyrosine kinase, ACK1. These compounds arose from efforts to rigidify an earlier series of N-aryl pyrimidine-5-carboxamides. The synthesis and structure-activity relationships of this new series of inhibitors are reported. The most promising compounds were also profiled for their pharmacokinetic properties.
Assuntos
Diaminas/antagonistas & inibidores , Inibidores Enzimáticos/síntese química , Proteínas Tirosina Quinases/antagonistas & inibidores , Pirazóis/química , Pirimidinas/química , Animais , Química Farmacêutica/métodos , Cristalografia por Raios X/métodos , Desenho de Fármacos , Inibidores Enzimáticos/farmacologia , Concentração Inibidora 50 , Masculino , Modelos Químicos , Conformação Molecular , Proteínas Tirosina Quinases/química , Ratos , Ratos Sprague-Dawley , Relação Estrutura-AtividadeRESUMO
A high-throughput screen resulted in the discovery of benzoxazepine 1, an EP2 antagonist possessing low microsomal stability and potent CYP3A4 inhibition. Modular optimization of lead compound 1 resulted in the discovery of benzoxazepine 52, a molecule with single-digit nM binding affinity for the EP2 receptor and significantly improved microsomal stability. It was devoid of CYP inhibition and was â¼4000-fold selective against the other EP receptors. Compound 52 was shown to have good PK properties in CD-1 mice and high CNS permeability in C57Bl/6s mice and Sprague-Dawley rats. In an ex vivo assay, it demonstrated the ability to increase the macrophage-mediated clearance of amyloid-beta plaques from brain slices in a dose-dependent manner.
Assuntos
Bioensaio/métodos , Encéfalo/efeitos dos fármacos , Macrófagos/efeitos dos fármacos , Oxazepinas/farmacologia , Fagocitose/efeitos dos fármacos , Placa Amiloide/metabolismo , Piridonas/farmacologia , Receptores de Prostaglandina E Subtipo EP2/antagonistas & inibidores , Animais , Encéfalo/citologia , Encéfalo/metabolismo , Macrófagos/citologia , Macrófagos/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Microssomos Hepáticos/efeitos dos fármacos , Microssomos Hepáticos/metabolismo , Estrutura Molecular , Oxazepinas/síntese química , Oxazepinas/farmacocinética , Piridonas/síntese química , Piridonas/farmacocinética , Ratos , Ratos Sprague-Dawley , Relação Estrutura-Atividade , Distribuição TecidualRESUMO
[reaction: see text] Pentacyclic triterpenoid natural product correolide (1) was converted to ketone 2 via ozonolysis. An unusual fragmentation reaction of ketone 2 with LiCl was discovered. This reaction is general among several similar substrates examined and appears to be specific for the correolide-type E-ring structure (ketone). A mechanism involving a retroaldol reaction, a nucleophilic opening of the epoxide, and a subsequent acetoxy elimination reaction was proposed.