RESUMO
This chapter will discuss the recent literature of macrocycles and drug-like property space moving beyond the rule of five (bRo5). Trends in chemical classes that fall within this definition are discussed and the impact of the latest technologies in the field assessed. The physicochemical properties, which have provided both successes and challenges, especially in scale-up, are discussed. A recent patent literature is reviewed and the chapter concludes with a perspective on the future of macrocyclic drug discovery.
Assuntos
Descoberta de Drogas , Compostos Macrocíclicos/farmacologia , Anti-Infecciosos/síntese química , Anti-Infecciosos/química , Anti-Infecciosos/farmacologia , Humanos , Compostos Macrocíclicos/síntese química , Compostos Macrocíclicos/química , Estrutura Molecular , Relação Estrutura-AtividadeRESUMO
A new concept in design of safe glucocorticoid therapy was introduced by conjugating potent glucocorticoid steroids with macrolides (macrolactonolides). These compounds were synthesized from various steroid 17ß-carboxylic acids and 9a-N-(3-aminoalkyl) derivatives of 9-deokso-9a-aza-9a-homoeritromicin A and 3-descladinosyl-9-deokso-9a-aza-9a-homoeritromicin A using stable alkyl chain. Combining property of macrolides to preferentially accumulate in immune cells, especially in phagocyte cells, with anti-inflammatory activity of classic steroids, we designed molecules which showed good anti-inflammatory activity in ovalbumin (OVA) induced asthma in rats. The synthesis, in vitro and in vivo anti-inflammatory activity of this novel class of compounds are described.
Assuntos
Anti-Inflamatórios/química , Anti-Inflamatórios/uso terapêutico , Asma/tratamento farmacológico , Macrolídeos/química , Macrolídeos/uso terapêutico , Esteroides/química , Esteroides/uso terapêutico , Animais , Anti-Inflamatórios/farmacocinética , Asma/induzido quimicamente , Ácidos Carboxílicos , Linhagem Celular , Desenho de Fármacos , Glucocorticoides/química , Glucocorticoides/farmacocinética , Glucocorticoides/uso terapêutico , Macrolídeos/farmacocinética , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Ratos , Ratos Endogâmicos BN , Esteroides/farmacocinéticaRESUMO
Cystic fibrosis (CF) is caused by mutations in the gene for the cystic fibrosis transmembrane conductance regulator (CFTR). With the discovery of Ivacaftor and Orkambi, it has been shown that CFTR function can be partially restored by administering one or more small molecules. These molecules aim at either enhancing the amount of CFTR on the cell surface (correctors) or at improving the gating function of the CFTR channel (potentiators). Here we describe the discovery of a novel potentiator GLPG1837, which shows enhanced efficacy on CFTR mutants harboring class III mutations compared to Ivacaftor, the first marketed potentiator. The optimization of potency, efficacy, and pharmacokinetic profile will be described.
Assuntos
Agonistas dos Canais de Cloreto/química , Fibrose Cística/tratamento farmacológico , Descoberta de Drogas , Proteínas Mutantes/efeitos dos fármacos , Aminofenóis/farmacocinética , Animais , Agonistas dos Canais de Cloreto/farmacocinética , Regulador de Condutância Transmembrana em Fibrose Cística/genética , Humanos , Mutação , Pirazóis/química , Pirazóis/farmacocinética , Quinolonas/farmacocinética , Ratos , Relação Estrutura-AtividadeRESUMO
Macrolides, polyketide natural products, and their 15-membered semi-synthetic derivatives are composed of substituted macrocyclic lactone ring and used primarily as potent antibiotics. Recently their usefulness was extended to antimalarial and anti-inflammatory area. Hybrid macrolides presented in this article are the next generation semi-synthetic compounds that combine pharmacophores from antibacterial, antimalarial and anti-inflammatory area with 14- and 15-membered azalide scaffolds. Antibacterial azalide hybrids with sulphonamides showed improved activity against resistant streptococci while quinolone conjugates demonstrated full coverage of respiratory pathogens including macrolide resistant strains and their efficacy was confirmed in mouse pneumonia model. Antimalarial macrolide hybrids, mainly involving (chloro)quinoline pharmacophores, showed outstanding activity against chloroquine resistant strains, favourable pharmacokinetics, promising in vivo efficacy as well as encouraging developmental potential. Anti-inflammatory hybrids were obtained by combining macrolides with corticosteroid and non-steroidal anti-inflammatory drugs. They were found active in in vivo animal models of locally induced inflammation, asthma, inflammatory bowel disease and rheumatoid arthritis and demonstrated improved safety over parent steroid drugs. Overall, macrolide hybrids possess significant potential to be developed as potent novel medicines in therapeutic areas of utmost pharmaceutical interest.
Assuntos
Antibacterianos/farmacologia , Anti-Inflamatórios não Esteroides/farmacologia , Antimaláricos/farmacologia , Descoberta de Drogas , Macrolídeos/farmacologia , Animais , Antibacterianos/síntese química , Antibacterianos/química , Anti-Inflamatórios não Esteroides/síntese química , Anti-Inflamatórios não Esteroides/química , Antimaláricos/síntese química , Antimaláricos/química , Bactérias/efeitos dos fármacos , Humanos , Inflamação/tratamento farmacológico , Macrolídeos/síntese química , Macrolídeos/química , Malária/tratamento farmacológicoRESUMO
In addition to antibacterial activity, some macrolide antibiotics, such as azithromycin and clarithromycin, also exhibit anti-inflammatory properties in vitro and in vivo, although the targets and mechanism(s) of action remain unknown. The aim of the present study was to identify protein targets of azithromycin and clarithromycin which could potentially explain their anti-inflammatory effects. Using chemical proteomics approach, based on compound-immobilized affinity chromatography, valosin containing protein (VCP) was identified as a potential target of the macrolides. Validation studies confirmed the interaction of macrolides and VCP and gave some structural characteristics of this interaction. Cell based assays however, including the use of gene silencing and the study of VCP specific cellular functions in J774.A1 (murine macrophage) and IB3-1 (human cystic fibrotic epithelial) cell lines, failed to confirm an association between the binding of the macrolides to VCP and anti-inflammatory effects. These findings suggest the absence of an abundant high affinity protein target and the potential involvement of other biological molecules in the anti-inflammatory activity of macrolides.
Assuntos
Adenosina Trifosfatases/metabolismo , Azitromicina/metabolismo , Azitromicina/farmacologia , Proteínas de Ciclo Celular/metabolismo , Claritromicina/metabolismo , Claritromicina/farmacologia , Adenosina Trifosfatases/deficiência , Adenosina Trifosfatases/genética , Animais , Antibacterianos/metabolismo , Antibacterianos/farmacologia , Anti-Inflamatórios/metabolismo , Anti-Inflamatórios/farmacologia , Proteínas de Ciclo Celular/deficiência , Proteínas de Ciclo Celular/genética , Linhagem Celular , Desenho de Fármacos , Inativação Gênica , Humanos , Camundongos , Ligação Proteica , Proteômica , Reprodutibilidade dos Testes , Proteína com ValosinaRESUMO
The novel racemic indolinospirobenzopyrans (5-7), indolinospironaphthopyrans (11-14) and indolinospironaphtho-1,4-oxazine (17) were synthesized by an aldol type of condensation of 1',3',3'-trimethyl-2 '-methyleneindoline and its 5-substituted derivatives with an appropriately substituted hydroxybenzaldehyde, hydroxynaphthaldehyde or nitrosonaphthol. An unequivocal proof of the stereostructures of 9 and 17 was obtained by the single-crystal X-ray diffraction method. A substituted indoline ring and the benzopyran ring in 9 and the naphtho-1,4-oxazine moiety in 17 are interconnected via the common chiral atom and positioned almost perpendicularly to each other. The five-membered 2,3-dihydropyrrolo moiety of the indoline ring adopts an envelope conformation in both structures. Of all the compounds of this series, spirobipyridopyran (1) inhibited specifically the growth of human melanoma (HBL) (IC(50): 0.9 microM) cells but not the growth of normal fibroblasts (WI38). Indolinospirobenzopyrans (8-10) showed significant cytostatic activities against all tumor cell lines. However, these compounds also exhibited a cytotoxic effect on normal human fibroblasts. The indolinospirobenzopyrans 4, 6-8, 10 and the indolinospironaphtho-1,4-oxazine 16 showed, albeit modest, selectivity as antiviral agents against varicella-zoster virus (VZV) and/or cytomegalovirus (CMV) (EC(50) within the concentration range of 1.0-12.6 microM).