ABSTRACT
The optimization for selectivity and central receptor occupancy for a series of spirocyclic azetidine-piperidine inverse agonists of the ghrelin receptor is described. Decreased mAChR muscarinic M2 binding was achieved by use of a chiral indane in place of a substituted benzylic group. Compounds with desirable balance of human in vitro clearance and ex vivo central receptor occupancy were discovered by incorporation of heterocycles. Specifically, heteroaryl rings with nitrogen(s) vicinal to the indane linkage provided the most attractive overall properties.
Subject(s)
Central Nervous System/drug effects , Receptors, Ghrelin/antagonists & inhibitors , Amino Acid Sequence , Animals , Binding Sites , Drug Inverse Agonism , Heterocyclic Compounds/chemistry , Heterocyclic Compounds/pharmacology , Humans , Indans/chemistry , Indans/pharmacology , Inhibitory Concentration 50 , Isomerism , Molecular Structure , Protein Binding/drug effects , Rats , Structure-Activity RelationshipABSTRACT
The discovery of spirocyclic piperidine-azetidine inverse agonists of the ghrelin receptor is described. The characterization and redressing of the issues associated with these compounds is detailed. An efficient three-step synthesis and a binding assay were relied upon as the primary means of rapidly improving potency and ADMET properties for this class of inverse agonist compounds. Compound 10 n bearing distributed polarity in the form of an imidazo-thiazole acetamide and a phenyl triazole is a unit lower in logP and has significantly improved binding affinity compared to the hit molecule 10a, providing support for further optimization of this series of compounds.
Subject(s)
Azetidines/chemistry , Piperidines/chemistry , Receptors, Ghrelin/agonists , Animals , Azetidines/chemical synthesis , Azetidines/pharmacokinetics , Drug Inverse Agonism , Humans , Microsomes, Liver/metabolism , Rats , Receptors, Ghrelin/metabolism , Structure-Activity RelationshipABSTRACT
NACCHO supports local public health agencies across the country in their efforts to implement smoke-free workplace ordinances in their communities. As the national voice of local public health, NACCHO also strives to strengthen and improve the health of our nation's communities through the tobacco prevention and control project. NACCHO provides a variety of tobacco-related tools and resources through its Web site (www.naccho.org), including the Tobacco Prevention and Control Learner's Guide; Smoke-free Policy Guidelines, a series of fact sheets co-authored by the Association of State and Territorial Health Officials (ASTHO) and the National Association of Local Board of Health (NALBOH); the Model Practices Database; Program and Funding Guidelines for Comprehensive Local Tobacco Control Programs, a document outlining the 7 components of a good tobacco control program; resources on social justice; NACCHO's Foundation Funding Guide, an online resource for local public health associations looking for grants from foundations; and links to other organizations. NACCHO also works to influence the development of integrated tobacco-related policy initiatives and their enforcement at the national and local level.Featured in this issue of the Journal of Public Health Management and Practice is an example of a success story of one of NACCHO's members in the area of smoke-free ordinances.
