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
A transdermal SARM has a potential to have therapeutic benefit through anabolic activity in muscle while sparing undesired effects of benign prostate hyperplasia (BPH) and liver-mediated decrease in HDL-C. 2-Chloro-4-[(2-hydroxy-2-methyl-cyclopentyl)amino]-3-methyl-benzonitrile 6 showed the desired muscle and prostate effects in a preclinical ORX rat model. Compound 6 had minimal effect on HDL-C levels in cynomolgus monkeys and showed human cadaver skin permeability, thus making it an effective tool for proof-of-concept studies in a clinical setting.
Subject(s)
Anabolic Agents/therapeutic use , Androgen Antagonists/therapeutic use , Aniline Compounds/therapeutic use , Muscular Atrophy/drug therapy , Nitriles/therapeutic use , Administration, Cutaneous , Anabolic Agents/administration & dosage , Anabolic Agents/chemical synthesis , Androgen Antagonists/administration & dosage , Androgen Antagonists/chemical synthesis , Aniline Compounds/administration & dosage , Aniline Compounds/chemical synthesis , Animals , Cholesterol, HDL/metabolism , Humans , Hypercholesterolemia/chemically induced , In Vitro Techniques , Liver/drug effects , Liver/metabolism , Macaca fascicularis , Male , Models, Molecular , Nitriles/administration & dosage , Nitriles/chemical synthesis , Orchiectomy , Prostatic Hyperplasia/chemically induced , Rats , Skin Absorption , Structure-Activity RelationshipABSTRACT
BACE1 is a key protease controlling the formation of amyloid ß, a peptide hypothesized to play a significant role in the pathogenesis of Alzheimer's disease (AD). Therefore, the development of potent and selective inhibitors of BACE1 has been a focus of many drug discovery efforts in academia and industry. Herein, we report the nonclinical and early clinical development of LY2886721, a BACE1 active site inhibitor that reached phase 2 clinical trials in AD. LY2886721 has high selectivity against key off-target proteases, which efficiently translates in vitro activity into robust in vivo amyloid ß lowering in nonclinical animal models. Similar potent and persistent amyloid ß lowering was observed in plasma and lumbar CSF when single and multiple doses of LY2886721 were administered to healthy human subjects. Collectively, these data add support for BACE1 inhibition as an effective means of amyloid lowering and as an attractive target for potential disease modification therapy in AD.
Subject(s)
Alzheimer Disease/drug therapy , Amyloid Precursor Protein Secretases/antagonists & inhibitors , Amyloid beta-Peptides/metabolism , Aspartic Acid Endopeptidases/antagonists & inhibitors , Heterocyclic Compounds, 2-Ring/pharmacology , Picolinic Acids/pharmacology , Protease Inhibitors/pharmacology , Amyloid beta-Peptides/blood , Amyloid beta-Peptides/cerebrospinal fluid , Animals , Disease Models, Animal , Dogs , Heterocyclic Compounds, 2-Ring/pharmacokinetics , Heterocyclic Compounds, 2-Ring/therapeutic use , Humans , Mice , Picolinic Acids/pharmacokinetics , Picolinic Acids/therapeutic use , Protease Inhibitors/pharmacokinetics , Protease Inhibitors/therapeutic useABSTRACT
The synthesis and initial SAR studies of novel, highly potent positive allosteric modulators of AMPA receptors based on 3-(4-tert-butylphenyl)-4-cyano-5-methylsulfanyl-thiophene-2-carboxylic acid (6a) are described. SAR studies at the thioether moiety indicated that substitution at this position was mandatory and better potency was achieved with small groups.
