ABSTRACT
N-Benzylic-substituted glycine sulfonamides that reversibly inhibit diacylglycerol (DAG) lipases are reported. Detailed herein are the structure activity relationships, profiling characteristics and physico-chemical properties for the first reported series of DAG lipase (DAGL) inhibitors that function without covalent attachment to the enzyme. Highly potent examples are presented that represent valuable tool compounds for studying DAGL inhibition and constitute important leads for future medicinal chemistry efforts.
Subject(s)
Enzyme Inhibitors/pharmacology , Glycine/pharmacology , Lipoprotein Lipase/antagonists & inhibitors , Sulfonamides/pharmacology , Dose-Response Relationship, Drug , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/chemistry , Glycine/analogs & derivatives , Glycine/chemistry , Humans , Lipoprotein Lipase/metabolism , Molecular Structure , Structure-Activity Relationship , Sulfonamides/chemical synthesis , Sulfonamides/chemistryABSTRACT
The present studies represent the first published report of a dopamine D1 positive allosteric modulator (PAM). D1 receptors have been proposed as a therapeutic target for the treatment of cognitive deficits associated with schizophrenia. However, the clinical utility of orthosteric agonist compounds is limited by cardiovascular side effects, poor pharmacokinetics, lack of D1 selectivity, and an inverted dose response. A number of these challenges may be overcome by utilization of a selective D1 PAM. The current studies describe two chemically distinct D1 PAMs: Compound A [1-((rel-1S,3R,6R)-6-(benzo[d][1,3]dioxol-5-yl)bicyclo[4.1.0]heptan-3-yl)-4-(2-bromo-5-chlorobenzyl)piperazine] and Compound B [rel-(9R,10R,12S)-N-(2,6-dichloro-3-methylphenyl)-12-methyl-9,10-dihydro-9,10-ethanoanthracene-12-carboxamide]. Compound A shows pure PAM activity, with an EC50 of 230 nM and agonist activity at the D2 receptor in D2-expressing human embryonic kidney cells. Compound B shows superior potency (EC50 of 43 nM) and selectivity for D1 versus D2 dopamine receptors. Unlike Compound A, Compound B is selective for human and nonhuman primate D1 receptors, but lacks activity at the rodent (rat and mouse) D1 receptors. Using molecular biology techniques, a single amino acid was identified at position 130, which mediates the species selectivity of Compound B. These data represent the first described D1-selective PAMs and define critical amino acids that regulate species selectivity.
Subject(s)
Allosteric Regulation/drug effects , Receptors, Dopamine D1/agonists , Receptors, Dopamine D2/agonists , Animals , CHO Cells , Cell Line , Cells, Cultured , Cricetulus , HEK293 Cells , Humans , Mice , Rats , Schizophrenia/drug therapyABSTRACT
Comprehensive structure activity relationship (SAR) studies were conducted on a focused screening hit, 2-(methylthio)-3-(phenylsulfonyl)-4H-pyrido[1,2-a]pyrimidin-4-imine (1, IC50: 4.0 nM), as 5-HT6 selective antagonists. Activity was improved some 2-4 fold when small, electron-donating groups were added to the central core as observed in 19, 20 and 26. Molecular docking of key compounds in a homology model of the human 5-HT6 receptor was used to rationalize our structure-activity relationship (SAR) findings. In pharmacokinetic experiments, compound 1 displayed good brain uptake in rats following intra-peritoneal administration, but limited oral bioavailability.
Subject(s)
Alzheimer Disease/drug therapy , Imines/pharmacokinetics , Receptors, Serotonin/therapeutic use , Animals , Humans , Imines/pharmacology , Molecular Docking Simulation , Rats , Structure-Activity RelationshipABSTRACT
A convergent synthesis route for the heterocyclic modification of a novel bicyclo[3.1.0]hexane NPY1 antagonist 2 was developed and the structure activity relationship of these modifications on NPY1 binding is reported. Two heterocyclic analogs 9 and 10 showed comparable Y1 binding potency to 2, but with improved aqueous solubility. Compound 9 demonstrated reduced spontaneous nocturnal food intake in a rat model when dosed ip. Compound 9 was also shown to be orally bioavailable and brain penetrable.
Subject(s)
Bridged Bicyclo Compounds/pharmacology , Heterocyclic Compounds/pharmacology , Receptors, Neuropeptide Y/antagonists & inhibitors , Administration, Oral , Animals , Bridged Bicyclo Compounds/administration & dosage , Bridged Bicyclo Compounds/chemistry , Dose-Response Relationship, Drug , Heterocyclic Compounds/administration & dosage , Heterocyclic Compounds/chemistry , Male , Molecular Structure , Rats , Rats, Sprague-Dawley , Structure-Activity RelationshipABSTRACT
A novel class of bicyclo[3.1.0]hexanylpiperazine neuropeptide Y (NPY) Y1 antagonists has been designed and synthesized. Scatchard binding analysis showed these compounds to be noncompetitive with [(125)I]PYY binding to the Y1 receptor. The most potent member, 1-((1α,3α,5α,6ß)-6-(3-ethoxyphenyl)-3-methylbicyclo[3.1.0]hexan-6-yl)-4-phenylpiperazine (2) had an IC50 = 62 nM and displayed excellent oral bioavailability in rat (% F po = 80), as well as good brain penetration (B/P ratio = 0.61). In a spontaneous nocturnal feeding study with male Sprague-Dawley rats, 2 significantly reduced food intake during a 12 h period.
ABSTRACT
An exploratory SAR study on a series of potent, non-apamin-displacing 4-(aminomethylaryl)pyrazolopyrimidine K(Ca) channel blockers is described and their selectivity against K(Ca) channel subtypes is reported. The most potent analog, 5-chloro-N-(thiophen-2-ylmethyl)pyrazolo[1,5-a]pyrimidin-7-amine (24) displayed sub-micromolar activity in both a thallium flux and whole-cell electrophysiology assay and did not displace apamin in a competitive binding study.
Subject(s)
Apamin/chemistry , Potassium Channel Blockers/chemistry , Pyrazoles/chemical synthesis , Pyrimidines/chemical synthesis , Binding, Competitive , Cell Line , Electrophysiology , Humans , Inhibitory Concentration 50 , Models, Chemical , Potassium Channels, Calcium-Activated/metabolism , Protein Isoforms , Pyrazoles/pharmacology , Pyrimidines/chemistry , Pyrimidines/pharmacology , Structure-Activity Relationship , Thallium/chemistryABSTRACT
An initial SAR study on a series of apamin-displacing 2-aminothiazole K(Ca)2 channel blockers is described. Potent inhibitors such as N-(4-methylpyridin-2-yl)-4-(pyridin-2-yl)thiazol-2-amine (13) are disclosed, and for select members of the series, the relationship between the observed activity in a thallium flux, a binding and a whole-cell electrophysiology assay is presented.
Subject(s)
Apamin/pharmacology , Potassium Channel Blockers/chemical synthesis , Potassium Channel Blockers/pharmacology , Pyridines/chemical synthesis , Pyridines/pharmacology , Small-Conductance Calcium-Activated Potassium Channels/antagonists & inhibitors , Thiazoles/chemical synthesis , Thiazoles/pharmacology , Combinatorial Chemistry Techniques , Molecular Structure , Potassium Channel Blockers/chemistry , Pyridines/chemistry , Structure-Activity Relationship , Thiazoles/chemistryABSTRACT
(E)-3-(Benzenesulfonyl)-2-(methylsulfanyl)pyrido[1,2-a]pyrimidin-4-ylidenamine (7) was found to be a potent and selective 5-HT(6) antagonist. A one-step synthesis of this compound is described.
