ABSTRACT
Leucine-rich repeat kinase 2 (LRRK2) is a large, multidomain protein which contains a kinase domain and GTPase domain among other regions. Individuals possessing gain of function mutations in the kinase domain such as the most prevalent G2019S mutation have been associated with an increased risk for the development of Parkinson's disease (PD). Given this genetic validation for inhibition of LRRK2 kinase activity as a potential means of affecting disease progression, our team set out to develop LRRK2 inhibitors to test this hypothesis. A high throughput screen of our compound collection afforded a number of promising indazole leads which were truncated in order to identify a minimum pharmacophore. Further optimization of these indazoles led to the development of MLi-2 (1): a potent, highly selective, orally available, brain-penetrant inhibitor of LRRK2.
Subject(s)
Enzyme Inhibitors/chemistry , Enzyme Inhibitors/pharmacology , Indazoles/chemistry , Indazoles/pharmacology , Leucine-Rich Repeat Serine-Threonine Protein Kinase-2/antagonists & inhibitors , Animals , Brain/metabolism , Enzyme Inhibitors/administration & dosage , Enzyme Inhibitors/pharmacokinetics , Humans , Indazoles/administration & dosage , Indazoles/pharmacokinetics , Leucine-Rich Repeat Serine-Threonine Protein Kinase-2/metabolism , Male , Molecular Docking Simulation , Parkinson Disease/drug therapy , Parkinson Disease/enzymology , Rats , Rats, WistarABSTRACT
A novel series of spiroimidazolone-based antagonists of the human glucagon receptor (hGCGR) has been developed. Our efforts have led to compound 1, N-((2H-tetrazol-5-yl)methyl)-4-((R)-1-((5r,8R)-8-(tert-butyl)-3-(3,5-dichlorophenyl)-2-oxo-1,4-diazaspiro[4.5]dec-3-en-1-yl)-4,4-dimethylpentyl)benzamide (SCH 900822), a potent hGCGR antagonist with exceptional selectivity over the human glucagon-like peptide-1 receptor. Oral administration of 1 lowered 24 h nonfasting glucose levels in imprinting control region mice on a high fat diet with diet-induced obesity following single oral doses of 3 and 10 mg/kg. Furthermore, compound 1, when dosed orally, was found to decrease fasting blood glucose at 30 mg/kg in a streptozotocin-treated, diet-induced obesity mouse pharmacodynamic assay and blunt exogenous glucagon-stimulated glucose excursion in prediabetic mice.
Subject(s)
Benzamides/chemical synthesis , Benzamides/pharmacology , Receptors, Glucagon/antagonists & inhibitors , Spiro Compounds/chemical synthesis , Spiro Compounds/pharmacology , Animals , Blood Glucose/metabolism , Cyclohexanones/chemistry , Cyclohexanones/pharmacology , Diabetes Mellitus, Experimental/drug therapy , Diabetes Mellitus, Type 2/drug therapy , Diet, High-Fat , Drug Discovery , Glucagon/pharmacology , Mice , Mice, Inbred ICR , Obesity/drug therapy , Prediabetic State/drug therapy , Prediabetic State/metabolism , Structure-Activity RelationshipABSTRACT
Vasopressin 1b (V1b) antagonists have been postulated as possible treatments for depression and anxiety. A novel series of potent and selective V1b antagonists has been identified starting from an in-house screen hit. The incorporation of a sulfonamide linker between a tetrahydroisoquinoline core and amino piperidine lead to the identification of a V1b antagonist with similar affinity for human and rat receptors. Further optimization of the right hand portion afforded potent V1b antagonists that possessed moderate to high selectivity over other receptors.
Subject(s)
Antidiuretic Agents/chemistry , Antidiuretic Hormone Receptor Antagonists , Quinolines/chemistry , Sulfonamides/chemistry , Animals , Antidiuretic Agents/chemical synthesis , Antidiuretic Agents/pharmacology , Humans , Quinolines/chemical synthesis , Quinolines/pharmacology , Rats , Receptors, Oxytocin/antagonists & inhibitors , Receptors, Oxytocin/metabolism , Receptors, Vasopressin/metabolism , Structure-Activity Relationship , Sulfonamides/chemical synthesis , Sulfonamides/pharmacologyABSTRACT
The unsymmetrical nicotinamide-N-oxide moiety in compound 1 was replaced with symmetrical isonicotinamides as well as 4,6-dimethyl pyrimidine-5-carboxamides. Compound 16 from the latter set reduced the number of rotamers, improved potency of inhibiting UIV entry, slightly diminished the affinity for the muscarine receptors and showed very good oral absorption.
Subject(s)
Anti-HIV Agents/chemical synthesis , Anti-HIV Agents/pharmacology , CCR5 Receptor Antagonists , HIV-1/drug effects , Piperazines/chemical synthesis , Piperazines/pharmacology , Administration, Oral , Animals , Anti-HIV Agents/pharmacokinetics , Area Under Curve , Chemical Phenomena , Chemistry, Physical , Half-Life , Heterocyclic Compounds/chemical synthesis , Heterocyclic Compounds/pharmacokinetics , Heterocyclic Compounds/pharmacology , Humans , Injections, Intravenous , Intestinal Absorption , Molecular Conformation , Piperazines/pharmacokinetics , Rats , Receptors, Muscarinic/drug effects , Structure-Activity RelationshipABSTRACT
The synthesis and muscarinic binding properties of compounds based on the 1-[4-(4-arylsulfonyl)phenylmethyl]-4-(1-aroyl-4-piperidinyl)-piperazine skeleton are described. For compounds, substituted with appropriately configured methyl groups at the benzylic center and at the piperazine 2-position, high levels of selective, M(2) subtype affinity could be obtained, particularly when the terminal N-aroyl residue was ortho-substituted.
Subject(s)
Piperazines/chemical synthesis , Piperazines/metabolism , Receptors, Muscarinic/metabolism , Binding Sites , Ligands , Molecular Structure , Piperazines/chemistry , Receptor, Muscarinic M1 , Receptor, Muscarinic M2 , Structure-Activity RelationshipABSTRACT
A novel series of 2-(R)-methyl-substituted piperazines (e.g., 2) is described. They are potent M(2) selective ligands that have >100-fold selectivity versus the M(1) receptor. In the rat microdialysis assay, compound 14 showed significantly enchanced levels of acetylcholine after oral administration.
