ABSTRACT
Inhibition of LRRK2 kinase activity with small molecules has emerged as a potential novel therapeutic treatment for Parkinson's disease. Herein we disclose the discovery of a 4-ethoxy-7H-pyrrolo[2,3-d]pyrimidin-2-amine series as potent LRRK2 inhibitors identified through a kinase-focused set screening. Optimization of the physicochemical properties and kinase selectivity led to the discovery of compound 7, which exhibited potent in vitro inhibition of LRRK2 kinase activity, good physicochemical properties and kinase selectivity across the kinome. Moreover, compound 7 was able to penetrate into the CNS, and in vivo pharmacology studies revealed significant inhibition of Ser935 phosphorylation in the brain of both rats (30 and 100â¯mg/kg) and mice (45â¯mg/kg) following oral administration.
Subject(s)
Drug Discovery , Leucine-Rich Repeat Serine-Threonine Protein Kinase-2/antagonists & inhibitors , Protein Kinase Inhibitors/pharmacology , Pyrimidines/pharmacology , Administration, Oral , Animals , Biological Availability , Brain/drug effects , Brain/metabolism , Dose-Response Relationship, Drug , Humans , Leucine-Rich Repeat Serine-Threonine Protein Kinase-2/metabolism , Mice , Molecular Structure , Phosphorylation/drug effects , Protein Kinase Inhibitors/administration & dosage , Protein Kinase Inhibitors/chemistry , Pyrimidines/chemistry , Rats , Serine/antagonists & inhibitors , Serine/metabolism , Structure-Activity RelationshipABSTRACT
We have discovered a novel complex crystal structure of the PHD2 enzyme with its inhibitor, the 2,8-diazaspiro[4.5]decan-1-one analogue 4b. The widely reported salt bridge between Arg383 of the enzyme and its inhibitors in all complex structures published thus far was not observed in our case. In our complex structure compound 4b forms several novel interactions with the enzyme, which include a hydrogen bond with Arg322, a π-cation interaction with Arg322, a π-π stacking with Trp389, and a π-π stacking with His313. Guided by the structural information, SAR studies were performed on the 2,8-diazaspiro[4.5]decan-1-one series leading to the discovery of compound 9p with high potency and good oral pharmacokinetic profile in mice.
Subject(s)
Aza Compounds/chemistry , Hypoxia-Inducible Factor-Proline Dioxygenases/antagonists & inhibitors , Prolyl-Hydroxylase Inhibitors/chemistry , Pyridines/chemistry , Administration, Oral , Animals , Binding Sites , Crystallography, X-Ray , Half-Life , Humans , Hypoxia-Inducible Factor-Proline Dioxygenases/metabolism , Male , Mice , Mice, Inbred C57BL , Molecular Docking Simulation , Prolyl-Hydroxylase Inhibitors/chemical synthesis , Prolyl-Hydroxylase Inhibitors/pharmacokinetics , Protein Binding , Protein Structure, Tertiary , Pyridines/chemical synthesis , Pyridines/pharmacokinetics , Spiro Compounds/chemical synthesis , Spiro Compounds/chemistry , Spiro Compounds/pharmacokinetics , Structure-Activity RelationshipABSTRACT
A novel series of benzoxazole-derived S1P(1) agonists were designed based on scaffold hopping molecular design strategy combined with computational approaches. Extensive SAR studies led to the discovery of compound 17d as a selective S1P(1) agonist (over S1P(3)) with high CNS penetration and favorable DMPK properties. 17d also demonstrated in vivo pharmacological efficacy to reduce blood lymphocyte in mice after oral administration.
Subject(s)
Benzoxazoles/chemical synthesis , Immunosuppressive Agents/chemical synthesis , Lymphocytes/drug effects , Receptors, Lysosphingolipid/agonists , Administration, Oral , Animals , Benzoxazoles/pharmacology , Binding Sites , Calcium/metabolism , Immunosuppressive Agents/pharmacology , Lymphocyte Count , Lymphocytes/cytology , Mice , Models, Molecular , Protein Binding , Receptors, Lysosphingolipid/metabolism , Sensitivity and Specificity , Sphingosine-1-Phosphate Receptors , Structure-Activity RelationshipABSTRACT
A novel series of 1,2,4-thiadiazole compounds was discovered as selective S1P(1) agonists. The extensive structure-activity relationship studies for these analogues were reported. Among them, 17g was identified to show high in vitro potency with reasonable free unbound fraction in plasma (F(u) > 0.5%), good brain penetration (BBR > 0.5), and desirable pharmacokinetic properties in mouse and rat. Oral administration of 1 mg/kg 17g resulted in significant peripheral lymphocytes reduction at 4 h after dose and rapid lymphocytes recovery at 24 h. 17g showed a transient lymphopenia profile in the repeated dose study in mouse. In addition, 17g also demonstrated efficacy comparable to that of FTY720 (1) in the mouse EAE model of MS.
Subject(s)
Immunosuppressive Agents/chemical synthesis , Immunosuppressive Agents/pharmacology , Multiple Sclerosis, Relapsing-Remitting/drug therapy , Receptors, Lysosphingolipid/agonists , Thiadiazoles/chemical synthesis , Thiadiazoles/pharmacology , Administration, Oral , Animals , Blood-Brain Barrier/drug effects , Blood-Brain Barrier/metabolism , Brain/drug effects , Brain/metabolism , Disease Models, Animal , Humans , Immunosuppressive Agents/chemistry , Immunosuppressive Agents/pharmacokinetics , Lymphocyte Count , Lymphocytes/drug effects , Lymphocytes/metabolism , Magnetic Resonance Spectroscopy , Male , Mice , Mice, Inbred C57BL , Multiple Sclerosis, Relapsing-Remitting/metabolism , Rats , Receptors, Lysosphingolipid/metabolism , Specific Pathogen-Free Organisms , Spectrometry, Mass, Electrospray Ionization , Structure-Activity Relationship , Thiadiazoles/chemistry , Thiadiazoles/pharmacokineticsABSTRACT
Novel indole-propionic acid derivatives were developed as sphingosine-1-phosphate (S1P) receptor agonists through a systematic SAR study. The optimized and S1P(3) selective S1P(1) agonist 9f induced peripheral blood lymphocyte reduction in vivo and has an excellent efficacy in mouse experimental autoimmune encephalomyelitis (EAE).
Subject(s)
Encephalomyelitis, Autoimmune, Experimental , Indoles/chemistry , Propionates/chemistry , Receptors, Lysosphingolipid/agonists , Animals , Down-Regulation/drug effects , Encephalomyelitis, Autoimmune, Experimental/therapy , Indoles/pharmacology , Lymphocytes/cytology , Lymphocytes/drug effects , Mice , Molecular Structure , Propionates/pharmacology , Structure-Activity RelationshipABSTRACT
A new and efficient samarium diiodide-promoted carbon-carbon bond fragmentation reaction of alpha-aminomethyl malonates, taking place normally at room temperature and generating the corresponding deaminomethylation products in 74-94% yields, is reported. The presence of the amino group is necessary for the success of the current transformation.
