ABSTRACT
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.
Subject(s)
Ligands , Nuclear Receptor Subfamily 1, Group F, Member 3/metabolism , Thiophenes/chemistry , Animals , Arthritis/chemically induced , Arthritis/drug therapy , Arthritis/pathology , Binding Sites , Crystallography, X-Ray , Disease Models, Animal , Drug Design , Female , Half-Life , Humans , Interleukin-17/genetics , Interleukin-17/metabolism , Leukocytes, Mononuclear/cytology , Leukocytes, Mononuclear/drug effects , Leukocytes, Mononuclear/metabolism , Mice , Molecular Dynamics Simulation , Nuclear Receptor Subfamily 1, Group F, Member 3/chemistry , Nuclear Receptor Subfamily 1, Group F, Member 3/genetics , Protein Binding , Structure-Activity Relationship , Thiophenes/metabolism , Thiophenes/pharmacology , Thiophenes/therapeutic useABSTRACT
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.
ABSTRACT
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.
Subject(s)
Benzopyrans/pharmacology , Chemistry, Pharmaceutical/methods , Estrogen Receptor beta/agonists , Selective Estrogen Receptor Modulators/pharmacology , Crystallography, X-Ray , Drug Design , Estrogen Receptor alpha/chemistry , Estrogen Receptor beta/chemistry , Female , Humans , Ligands , Male , Models, Chemical , Models, Molecular , Structure-Activity Relationship , Transcription Factors/metabolismABSTRACT
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.
Subject(s)
Estrogen Receptor beta/agonists , Flavonoids/chemical synthesis , Prostatic Hyperplasia/drug therapy , Selective Estrogen Receptor Modulators/chemical synthesis , Animals , Binding Sites , Crystallography, X-Ray , Estrogen Receptor alpha/chemistry , Estrogen Receptor beta/chemistry , Estrogens , Flavonoids/chemistry , Flavonoids/pharmacology , Humans , Ligands , Male , Mice , Models, Molecular , Molecular Structure , Prostate/drug effects , Prostate/pathology , Prostatic Hyperplasia/pathology , Selective Estrogen Receptor Modulators/chemistry , Selective Estrogen Receptor Modulators/pharmacology , Structure-Activity RelationshipABSTRACT
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.
Subject(s)
Adipose Tissue/drug effects , Eating/drug effects , Receptors, G-Protein-Coupled/agonists , Adipose Tissue/physiology , Administration, Oral , Animals , Drug Evaluation, Preclinical , Eating/physiology , Ghrelin , Male , Peptide Hormones/chemistry , Peptide Hormones/pharmacology , Rats , Rats, Long-Evans , Receptors, G-Protein-Coupled/physiology , Receptors, GhrelinABSTRACT
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.
