RESUMO
Steroidal glucocorticoids (GR agonists) have been widely used for the topical treatment of skin disorders, including atopic dermatitis. They are a very effective therapy, but they are associated with both unwanted local effects in the skin (skin thinning/atrophy) and systemic side effects. These effects can limit the long-term utility of potent steroids. Here we report on a topically delivered non-steroidal GR agonist, that has the potential to deliver high efficacy in the skin, but due to rapid metabolism in the blood & liver ("dual-soft") it should have greater systemic safety than existing treatments. In addition, compared to less selective steroidal GR agonists, the new non-steroidal Selective Glucocorticoid Agonists (SEGRAs) have the potential to avoid the skin atrophy observed with existing topical steroids. Due to its potential for reduced skin atrophy and low systemic exposure, LEO 134310 (17) may be suitable for long term topical treatment of skin diseases such as atopic dermatitis and psoriasis.
Assuntos
Receptores de Glucocorticoides/agonistas , Esteroides/química , Administração Tópica , Dermatite Atópica/tratamento farmacológico , Desenho de Fármacos , Estabilidade de Medicamentos , Meia-Vida , Humanos , Indazóis/química , Indazóis/metabolismo , Indazóis/farmacologia , Indazóis/uso terapêutico , Leucócitos Mononucleares/citologia , Leucócitos Mononucleares/efeitos dos fármacos , Leucócitos Mononucleares/metabolismo , Lipopolissacarídeos/farmacologia , Psoríase/tratamento farmacológico , Receptores de Glucocorticoides/metabolismo , Esteroides/metabolismo , Esteroides/farmacologia , Esteroides/uso terapêutico , Relação Estrutura-Atividade , Fator de Necrose Tumoral alfa/metabolismoRESUMO
A class of potent, nonsteroidal, selective indazole ether-based glucocorticoid receptor modulators (SGRMs) was developed for the inhaled treatment of respiratory diseases. Starting from an orally available compound with demonstrated anti-inflammatory activity in rat, a soft-drug strategy was implemented to ensure rapid elimination of drug candidates to minimize systemic GR activation. The first clinical candidate 1b (AZD5423) displayed a potent inhibition of lung edema in a rat model of allergic airway inflammation following dry powder inhalation combined with a moderate systemic GR-effect, assessed as thymic involution. Further optimization of inhaled drug properties provided a second, equally potent, candidate, 15m (AZD7594), that demonstrated an improved therapeutic ratio over the benchmark inhaled corticosteroid 3 (fluticasone propionate) and prolonged the inhibition of lung edema, indicating potential for once-daily treatment.
Assuntos
Acetamidas/uso terapêutico , Indazóis/uso terapêutico , Edema Pulmonar/tratamento farmacológico , Receptores de Glucocorticoides/efeitos dos fármacos , Administração por Inalação , Idoso , Animais , Relação Dose-Resposta a Droga , Humanos , Espectrometria de Massas , Pós , Espectroscopia de Prótons por Ressonância Magnética , RatosRESUMO
We report the discovery of highly potent and selective non-steroidal glucocorticoid receptor modulators with PK properties suitable for inhalation. A high throughput screen of the AstraZeneca compound collection identified sulfonamide 3 as a potent non-steroidal glucocorticoid receptor ligand. Further optimization of this lead generated indazoles 30 and 48 that were progressed to characterization in in vivo models. X-ray crystallography was used to gain further insight into the binding mode of selected ligands.
Assuntos
Anti-Inflamatórios não Esteroides/farmacologia , Descoberta de Drogas , Receptores de Glucocorticoides/antagonistas & inibidores , Sulfonamidas/farmacologia , Anti-Inflamatórios não Esteroides/síntese química , Anti-Inflamatórios não Esteroides/química , Cristalografia por Raios X , Relação Dose-Resposta a Droga , Ensaios de Triagem em Larga Escala , Humanos , Ligantes , Modelos Moleculares , Estrutura Molecular , Relação Estrutura-Atividade , Sulfonamidas/síntese química , Sulfonamidas/químicaRESUMO
The large scale motion of proteins, or covalently bonded polymers in general, is governed by the dynamics of the torsion angles, with bond lengths and bond angles kept approximately constant. In the present work, the Lagrangian equations of torsion motion are derived for a general macromolecule. The dynamics is implemented numerically for a test protein, using the velocity Verlet method as the integrator. The results indicate time steps of up to about 30 fs can be used for short time (up to at least 20 ps) simulations, before the dynamics and energy start to differ significantly from results obtained with smaller time steps. For longer time simulations, up to 1000 ps, a time step of 10 fs is relatively safe.
Assuntos
Modelos Químicos , Polímeros/química , Proteínas/química , Simulação por Computador , Modelos Moleculares , Conformação Proteica , Torção MecânicaRESUMO
The small-amplitude conformational changes in macromolecules can be described by the changes in bond lengths and bond angles. The descriptors of large scale changes are torsions. We present a recursive algorithm, in which a bond vector is explicitly written in terms of these internal, or polyspherical coordinates, in a local frame defined by two other bond vectors and their cross product. Conformations of linear and branched molecules, as well as molecules containing rings can be described in this way. The orientation of the molecule is described by the orientation of a body frame. It is parametrized by the instantaneous rotation angle, and the two angles that parametrize the orientation of the instantaneous rotation axis. The reason not to use more conventional Euler angles is due to the fact that Euler angles are not well-defined in gimbal lock (i.e., when a body axis becomes aligned with its space fixed counter part). The position of the molecule is parametrized by its center of mass. Original and calculated positions are compared for several proteins, containing up to about 100,000 atoms.
