ABSTRACT
The synthesis and diversification of a densely functionalized azetidine ring system to gain access to a wide variety of fused, bridged, and spirocyclic ring systems is described. The in vitro physicochemical and pharmacokinetic properties of representative library members are measured in order to evaluate the use of these scaffolds for the generation of lead-like molecules to be used in targeting the central nervous system. The solid-phase synthesis of a 1976-membered library of spirocyclic azetidines is also described.
Subject(s)
Azetidines/pharmacokinetics , Central Nervous System/drug effects , Small Molecule Libraries/chemical synthesis , Small Molecule Libraries/pharmacokinetics , Spiro Compounds/chemical synthesis , Spiro Compounds/pharmacokinetics , Animals , Azetidines/blood , Azetidines/chemical synthesis , Caco-2 Cells , Cell Membrane Permeability/drug effects , Central Nervous System/cytology , Endothelial Cells/drug effects , Humans , Mice , Molecular Structure , Solubility , Spiro Compounds/blood , StereoisomerismABSTRACT
Positive allosteric modulation of metabotropic glutamate receptor 5 (mGluR5) is regarded as a potential novel treatment for schizophrenic patients. Herein we report the synthesis and SAR of 4-aryl piperazine and piperidine amides as potent mGluR5 positive allosteric modulators (PAMs). Several analogs have excellent activity and desired drug-like properties. Compound 2b was further characterized as a PAM using several in vitro experiments, and produced robust activity in several preclinical animal models.
Subject(s)
Amides/chemistry , Piperazines/chemistry , Piperidines/chemistry , Receptors, Metabotropic Glutamate/chemistry , Allosteric Regulation , Amides/chemical synthesis , Amides/therapeutic use , Humans , Microsomes, Liver/metabolism , Piperazine , Receptor, Metabotropic Glutamate 5 , Receptors, Metabotropic Glutamate/metabolism , Schizophrenia/drug therapy , Structure-Activity RelationshipABSTRACT
Further structure activity relationship studies on a previously reported 8-azabicyclo[3.2.1]octan-3-yloxy-benzamide series of potent and selective kappa opioid receptor antagonists is discussed. Modification of the pendant N-substitution to include a cyclohexylurea moiety produced analogs with greater in vitro opioid and hERG selectivity such as 12 (kappa IC50=172 nM, mu:kappa ratio=93, delta:kappa ratio=>174, hERG IC50=>33 microM). Changes to the linker conformation and identity as well as to the benzamide ring moiety were also investigated.
Subject(s)
Antidepressive Agents/chemistry , Antidepressive Agents/pharmacology , Benzamides/chemistry , Benzamides/pharmacology , Receptors, Opioid, kappa/antagonists & inhibitors , Receptors, Opioid, kappa/metabolism , Animals , Antidepressive Agents/chemical synthesis , Antidepressive Agents/pharmacokinetics , Benzamides/chemical synthesis , Benzamides/pharmacokinetics , Brain/metabolism , Bridged Bicyclo Compounds/chemical synthesis , Bridged Bicyclo Compounds/chemistry , Bridged Bicyclo Compounds/pharmacokinetics , Bridged Bicyclo Compounds/pharmacology , Depressive Disorder, Major/drug therapy , Humans , Microsomes, Liver/metabolism , Rats , Structure-Activity RelationshipABSTRACT
Initial high throughput screening efforts identified highly potent and selective kappa opioid receptor antagonist 3 (κ IC(50)=77 nM; µ:κ and δ:κ IC(50) ratios>400) which lacked CNS exposure in vivo. Modification of this scaffold resulted in development of a series of 8-azabicyclo[3.2.1]octan-3-yloxy-benzamides showing potent and selectivity κ antagonism as well as good brain exposure. Analog 6c (κ IC(50)=20 nM; µ:κ=36, δ:κ=415) was also shown to reverse κ-agonist induced rat diuresis in vivo.
Subject(s)
Benzamides/chemistry , Receptors, Opioid, kappa/antagonists & inhibitors , Tropanes/chemistry , Animals , Benzamides/chemical synthesis , Benzamides/pharmacokinetics , Cell Line, Tumor , Diuresis/drug effects , Drug Evaluation, Preclinical , High-Throughput Screening Assays , Humans , Microsomes, Liver/metabolism , Rats , Receptors, Opioid, kappa/metabolism , Structure-Activity Relationship , Tropanes/chemical synthesis , Tropanes/pharmacokineticsABSTRACT
The editorial office and authors have requested that this article be withdrawn due to additional information discovered regarding the patient in which the article was written. The full Elsevier Policy on Article Withdrawal can be found at http://www.elsevier.com/locate/withdrawalpolicy.
ABSTRACT
OBJECTIVES: To estimate the prevalence of developmental delay and service use among children in the child welfare system and to identify factors that influence these outcomes. DESIGN: A descriptive study using wave 1 of the National Survey of Child and Adolescent Well-Being. PARTICIPANTS AND SETTING: Children aged 0 to 10 years (n = 4324) and their caregivers were interviewed within 60 days of a report being made to the child welfare system. Children's development was measured directly using standardized assessment tools. Three questions from the caregiver interviews estimated receipt of developmental services. MAIN EXPOSURES: Subjects were characterized as having developmental delay if any developmental measure fell more than 2 SDs below the mean. Prevalence of developmental delay and service use by age group, type of maltreatment, type of placement, race, sex, and income were reported. Odds that children aged 0 to 2, 3 to 5, and 6 to 10 years with developmental delay would receive developmental services were calculated using weighted logistic regression. main outcome measure: Receipt of developmental services by children with developmental delay. RESULTS: Younger children aged 0 to 2 and 3 to 5 years had higher rates, 33% and 36%, respectively, of developmental delay than school-aged children (13%) (P<.01). Despite their high prevalence of developmental delay, children aged 0 to 2 years were less likely to receive developmental services than preschool-aged children (odds ratio, 2.4; 95% confidence interval, 1.6-3.7) or school-aged children (odds ratio, 4.2; 95% confidence interval, 2.9-6.0). CONCLUSIONS: Rates of developmental delay are high and developmental services are underused, particularly by young children in the child welfare system. Strategies for overcoming barriers to using early intervention services should be implemented.