RESUMO
The Th17 pathway has been implicated in autoimmune diseases. The retinoic acid receptor-related orphan receptor C2 (RORγt) is a master regulator of Th17 cells and controls the expression of IL-17A. RORγt is expressed primarily in IL-17A-producing lymphoid cells. Here we describe a virtual screen of the ligand-binding pocket and subsequent screen in a binding assay that identified the 1-benzyl-4',5'-dihydrospiro[piperidine-4,7'-thieno[2,3-c]pyran]-2'-carboxamide scaffold as a starting point for optimization of binding affinity and functional activity guided by structure-based design. Compound 12 demonstrated activity in a mouse PK/PD model and efficacy in an inflammatory arthritis mouse model that were used to define the level and duration of target engagement required for efficacy in vivo. Further optimization to improve ADME and physicochemical properties with guidance from simulations and modeling provided compound 22, which is projected to achieve the level and duration of target engagement required for efficacy in the clinic.
Assuntos
Ligantes , Membro 3 do Grupo F da Subfamília 1 de Receptores Nucleares/metabolismo , Tiofenos/química , Animais , Artrite/induzido quimicamente , Artrite/tratamento farmacológico , Artrite/patologia , Sítios de Ligação , Cristalografia por Raios X , Modelos Animais de Doenças , Desenho de Fármacos , Feminino , Meia-Vida , Humanos , Interleucina-17/genética , Interleucina-17/metabolismo , Leucócitos Mononucleares/citologia , Leucócitos Mononucleares/efeitos dos fármacos , Leucócitos Mononucleares/metabolismo , Camundongos , Simulação de Dinâmica Molecular , Membro 3 do Grupo F da Subfamília 1 de Receptores Nucleares/química , Membro 3 do Grupo F da Subfamília 1 de Receptores Nucleares/genética , Ligação Proteica , Relação Estrutura-Atividade , Tiofenos/metabolismo , Tiofenos/farmacologia , Tiofenos/uso terapêuticoRESUMO
Benzopyran selective estrogen receptor beta agonist-1 (SERBA-1) shows potent, selective binding and agonist function in estrogen receptor beta (ERbeta) in vitro assays. X-ray crystal structures of SERBA-1 in ERalpha and beta help explain observed beta-selectivity of this ligand. SERBA-1 in vivo demonstrates involution of the ventral prostate in CD-1 mice (ERbeta effect), while having no effect on gonadal hormone levels (ERalpha effect) at 10x the efficacious dose, consistent with in vitro properties of this molecule.
Assuntos
Receptor beta de Estrogênio/agonistas , Flavonoides/síntese química , Hiperplasia Prostática/tratamento farmacológico , Moduladores Seletivos de Receptor Estrogênico/síntese química , Animais , Sítios de Ligação , Cristalografia por Raios X , Receptor alfa de Estrogênio/química , Receptor beta de Estrogênio/química , Estrogênios , Flavonoides/química , Flavonoides/farmacologia , Humanos , Ligantes , Masculino , Camundongos , Modelos Moleculares , Estrutura Molecular , Próstata/efeitos dos fármacos , Próstata/patologia , Hiperplasia Prostática/patologia , Moduladores Seletivos de Receptor Estrogênico/química , Moduladores Seletivos de Receptor Estrogênico/farmacologia , Relação Estrutura-AtividadeRESUMO
We report the synthesis and characterization of novel 3-aryl indoles as potent and efficacious progesterone receptor (PR) antagonists with potential for the treatment of uterine fibroids. These compounds demonstrated excellent selectivity over other steroid nuclear hormone receptors such as the mineralocorticoid receptor (MR). They were prepared from 2-bromo-6-nitro indole in four to six steps using a Suzuki cross-coupling as the key step. Compound 8f was orally active in the complement 3 model of progesterone antagonism in the rat uterus and demonstrated partial antagonism in the McPhail model of progesterone activity.
RESUMO
Benzopyrans are selective estrogen receptor (ER) beta agonists (SERBAs), which bind the ER subtypes alpha and beta in opposite orientations. Here we describe structure-activity relationship studies that led to the discovery of bezopyran 5b. X-ray crystal structures of 5b and a non-selective analog 5c in ERalpha help explain the observed selectivity of the benzopyran platform.
Assuntos
Benzopiranos/farmacologia , Química Farmacêutica/métodos , Receptor beta de Estrogênio/agonistas , Moduladores Seletivos de Receptor Estrogênico/farmacologia , Cristalografia por Raios X , Desenho de Fármacos , Receptor alfa de Estrogênio/química , Receptor beta de Estrogênio/química , Feminino , Humanos , Ligantes , Masculino , Modelos Químicos , Modelos Moleculares , Relação Estrutura-Atividade , Fatores de Transcrição/metabolismoRESUMO
The pharmacology and SAR of representative equine estogens is described. 17alpha-Dihydroequilenin was found to prevent bone loss after 5 weeks of oral administration to ovariectomized rats. The stereochemical significance of the D-ring and the C/D ring juncture was investigated with a series of benzothiophene-based equilenin analogues.
Assuntos
Equilina/farmacologia , Congêneres do Estradiol/farmacologia , Animais , Equilina/análogos & derivados , Equilina/síntese química , Equilina/química , Congêneres do Estradiol/administração & dosagem , Congêneres do Estradiol/síntese química , Congêneres do Estradiol/química , Feminino , Modelos Moleculares , Conformação Molecular , Tamanho do Órgão/efeitos dos fármacos , Ovariectomia , Ratos , Estereoisomerismo , Relação Estrutura-Atividade , Útero/anatomia & histologia , Útero/efeitos dos fármacosRESUMO
2-(2-Amino-2-methyl-propionylamino)-5-phenyl-pentanoic acid [1-[1-(4-methoxy-phenyl)-1-methyl-2-oxo-2-pyrrolidin-1-yl-ethyl]-1H-imidazol-4-yl]-amide (LY444711, 6) is an orally active ghrelin agonist that binds with high affinity to and is a potent activator of the growth hormone secretagogue receptor 1a (GHS-R1a) receptor. In rat models of feeding behavior and pharmacology, 6 creates a positive energy balance and induces adiposity by stimulating food consumption and sparing fat utilization. As an orally active ghrelin agonist, 6 represents a new pharmacological tool to investigate the orexigenic role of ghrelin in regulating energy homeostasis.