RESUMO
Hematological cancers are among the most common cancers in adults and children. Despite significant improvements in therapies, many patients still succumb to the disease. Therefore, novel therapies are needed. The Wiskott-Aldrich syndrome protein (WASp) family regulates actin assembly in conjunction with the Arp2/3 complex, a ubiquitous nucleation factor. WASp is expressed exclusively in hematopoietic cells and exists in two allosteric conformations: autoinhibited or activated. Here, we describe the development of EG-011, a first-in-class small molecule activator of the WASp auto-inhibited form. EG-011 possesses in vitro and in vivo anti-tumor activity as a single agent in lymphoma, leukemia, and multiple myeloma, including models of secondary resistance to PI3K, BTK, and proteasome inhibitors. The in vitro activity was confirmed in a lymphoma xenograft. Actin polymerization and WASp binding was demonstrated using multiple techniques. Transcriptome analysis highlighted homology with drugs-inducing actin polymerization.
RESUMO
Pharmacophore-based structural identification, synthesis, and structure-activity relationships of a new class of muscarinic M3 receptor antagonists, the diaryl imidazolidin-2-one derivatives, are described. The versatility of the discovered scaffold allowed for several structural modifications that resulted in the discovery of two distinct classes of compounds, specifically a class of tertiary amine derivatives (potentially useful for the treatment of overactive bladder by oral administration) and a class of quaternary ammonium salt derivatives (potentially useful for the treatment of respiratory diseases by the inhalation route of administration). In this paper, we describe the synthesis and biological activity of tertiary amine derivatives. For these compounds, selectivity for the M3 receptor toward the M2 receptor was crucial, because the M2 receptor subtype is mainly responsible for adverse systemic side effects of currently marketed muscarinic antagonists. Compound 50 showed the highest selectivity versus M2 receptor, with binding affinity for M3 receptor Ki = 4.8 nM and for M2 receptor Ki = 1141 nM. Functional in vitro studies on selected compounds confirmed the antagonist activity toward the M3 receptor and functional selectivity toward the M2 receptor.
Assuntos
Imidazolidinas/síntese química , Receptor Muscarínico M3/antagonistas & inibidores , Administração Oral , Animais , Função Atrial/efeitos dos fármacos , Células CHO , Células CACO-2 , Permeabilidade da Membrana Celular , Cricetinae , Cricetulus , Feminino , Humanos , Imidazolidinas/química , Imidazolidinas/farmacologia , Técnicas In Vitro , Masculino , Camundongos , Microssomos/metabolismo , Modelos Moleculares , Contração Muscular/efeitos dos fármacos , Músculo Liso/efeitos dos fármacos , Músculo Liso/fisiologia , Ensaio Radioligante , Ratos , Receptor Muscarínico M2/antagonistas & inibidores , Relação Estrutura-Atividade , Bexiga Urinária/efeitos dos fármacos , Bexiga Urinária/fisiologiaRESUMO
Synthesis and biological activity of a novel class of quaternary ammonium salt muscarinic M3 receptor antagonists, showing high selectivity versus the M2 receptor, are described. Selected compounds exhibited potent anticholinergic properties, in isolated guinea-pig trachea, and good functional selectivity for trachea over atria. In vivo, the same compounds potently inhibited acetylcholine-induced bronchoconstriction after intratracheal administration in the guinea pig.
Assuntos
Broncodilatadores/química , Imidazolidinas/síntese química , Compostos de Amônio Quaternário/síntese química , Receptor Muscarínico M3/antagonistas & inibidores , Animais , Broncoconstrição/efeitos dos fármacos , Broncodilatadores/síntese química , Broncodilatadores/farmacologia , Células CHO , Cricetinae , Cricetulus , Cobaias , Humanos , Imidazolidinas/química , Imidazolidinas/farmacologia , Técnicas In Vitro , Masculino , Contração Muscular/efeitos dos fármacos , Músculo Liso/efeitos dos fármacos , Músculo Liso/fisiologia , Contração Miocárdica/efeitos dos fármacos , Compostos de Amônio Quaternário/química , Compostos de Amônio Quaternário/farmacologia , Ensaio Radioligante , Relação Estrutura-Atividade , Traqueia/efeitos dos fármacos , Traqueia/fisiologiaRESUMO
The first steps in the selection process of a new anti-inflammatory drug for the inhaled treatment of asthma and chronic obstructive pulmonary disease are herein described. A series of novel ester derivatives of 1-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-(3,5-dichloropyridin-4-yl) ethanol have been synthesized and evaluated for inhibitory activity toward cAMP-specific phosphodiesterase-4 (PDE4). In particular, esters of variously substituted benzoic acids were extensively explored, and structural modification of the alcoholic and benzoic moieties were performed to maximize the inhibitory potency. Several compounds with high activity in cell-free and cell-based assays were obtained. Through the evaluation of opportune in vitro ADME properties, a potential candidate suitable for inhaled administration in respiratory diseases was identified and tested in an in vivo model of pulmonary inflammation, proving its efficacy.
Assuntos
Anti-Inflamatórios não Esteroides/síntese química , Asma/tratamento farmacológico , Benzoatos/síntese química , Pneumopatias Obstrutivas/tratamento farmacológico , Inibidores da Fosfodiesterase 4/síntese química , Sulfonamidas/síntese química , para-Aminobenzoatos/síntese química , Administração por Inalação , Animais , Anti-Inflamatórios não Esteroides/química , Anti-Inflamatórios não Esteroides/farmacologia , Benzoatos/química , Benzoatos/farmacologia , Linhagem Celular , Doença Crônica , Cristalografia por Raios X , Eosinofilia/tratamento farmacológico , Eosinofilia/imunologia , Eosinofilia/patologia , Ésteres , Cobaias , Humanos , Leucócitos Mononucleares/efeitos dos fármacos , Leucócitos Mononucleares/enzimologia , Pulmão/efeitos dos fármacos , Pulmão/imunologia , Pulmão/patologia , Simulação de Acoplamento Molecular , Ovalbumina , Inibidores da Fosfodiesterase 4/química , Inibidores da Fosfodiesterase 4/farmacologia , Conformação Proteica , Ratos , Estereoisomerismo , Relação Estrutura-Atividade , Sulfonamidas/química , Sulfonamidas/farmacologia , para-Aminobenzoatos/química , para-Aminobenzoatos/farmacologiaRESUMO
A new pyridine-2,6-bis(oxazoline) (4) has been easily synthesised from the reaction of (1S,2S)-2-amino-1-phenylpropane-1,3-diol (1) and dimethyl pyridine-2,6-dicarboximidate (2), followed by TIPS (TIPS=triisopropylsilyl) protection of the 4'-CH2OH group. The catalysts derived from 4 and eight lanthanide(III) triflates have been tested over three reactions involving 3-acryloyl- and 3-crotonoyloxazolidinones (5 a,b): the Diels-Alder (DA) reaction with cyclopentadiene, the 1,3-dipolar cycloaddition with diphenyl nitrone and the Mukaiyama-Michael reaction with 2-trimethylsilyloxyfuran. Several reactions exhibit very good enantioselectivity (ee>90 %), and the opposite enantiomers can be easily obtained simply by changing the cation. This specific feature of the ligand can be appreciated in the DA reaction of 5 a, since the catalyst [Sc(III)4] gives the adduct (2'S)-9 a with 99 % ee, whereas the catalyst [Y(III)4] gives the opposite enantiomer with 95 % ee. A rationale of the enantioselectivity is proposed on the basis of the NMR spectra of La-based complexes involving 4 and 5 as ligands.
RESUMO
The Diels-Alder reaction of cyclopentadiene with acryloyl-1,3-oxazolidin-2-one is catalyzed by (R,R)-i-Pr- and (R,R)-Ph-pybox (5 and 6)/lanthanide(III) triflate complexes. The enantioselectivity of the reaction is influenced by 4 A molecular sieves; moreover, the absolute sense of the enantioselection was found to be a function of the nature of the substituents on the chiral ligand (e.g., aromatic vs alkyl groups) as well as of the specific cation employed. In particular, seven lanthanide triflates were tested and a regular variation of the enantioselectivity as a function of the cation ionic radius was evidenced. The different sense of induction can be rationalized by assuming two competitive reacting complexes with different coordination number, which favor the attack on the opposite heterotopic faces of the coordinated dienophile.