ABSTRACT
Nicotinamides of benzyl-substituted 4-aminopiperidines and their seven-membered analogs of generic structure 2 and 2' have been discovered as potent and selective SST5 antagonists. The activity (K(i)) ranges from 2.4 to 436 nM. Most compounds exhibit decent physicochemical properties and follow a clear SAR pattern. Interestingly enough, the receptor is strongly enantiodiscriminating and binds in the amino-azepane-series only the (R)-enantiomer.
Subject(s)
Benzyl Compounds/chemistry , Niacinamide/chemistry , Receptors, Somatostatin/antagonists & inhibitors , Niacinamide/chemical synthesis , Niacinamide/pharmacology , Piperidines/chemistry , Receptors, Somatostatin/metabolism , Stereoisomerism , Structure-Activity RelationshipABSTRACT
BACKGROUND: Somatostatin regulates numerous endocrine processes, including glucose homeostasis. The contribution and effects of the 5 somatostatin receptors are still unclear, in part due to the lack of suitable subtype specific receptor antagonists. We explored the effects of two novel, non-peptidic, orally bioavailable somatostatin receptor subtype 5 antagonists named Compound A and Compound B on glycemia in animal models of type 2 diabetes after an initial in vitro characterization. METHODS AND RESULTS: Compound A led to a dose-dependent decrease in glucose and insulin excursions during an OGTT in Zucker (fa/fa) rats after single treatment by up to 17% and 49%, respectively. Diet-induced obese mice showed after three weeks treatment with compounds A and B a dose-dependent decrease of the glucose excursion of up to 45% and 37%, respectively. In contrast to the acute effect observed in Zucker rats, Compound A showed a dose-dependent insulin increase by up to 72%, whereas body weight, liver triglycerides, ALT and AST were dose-dependently decreased. CONCLUSIONS: SSTR5 antagonists have the potential for short- and long-term improvements of the glucose homeostasis in rodent models of type 2 diabetes. Further work on the mechanism and the relevance for human disease is warranted.
Subject(s)
Blood Glucose/metabolism , Diabetes Mellitus, Experimental/drug therapy , Hypoglycemic Agents/pharmacology , Obesity/drug therapy , Receptors, Somatostatin/antagonists & inhibitors , Animals , Body Weight/drug effects , CHO Cells , Cricetinae , Cricetulus , Diabetes Mellitus, Experimental/blood , Dose-Response Relationship, Drug , Homeostasis/drug effects , Humans , Liver/metabolism , Mice , Obesity/blood , Rats , Rats, Zucker , Receptors, Somatostatin/metabolism , Triglycerides/metabolismABSTRACT
SAR studies of a recently described SST5R selective benzoxazole piperidine lead series are described with particular focus on the substitution pattern on the benzyl and benzoxazole side-chains. Introduction of a second meta substituent at the benzyl unit significantly lowers residual hH1 activity and insertion of substituents onto the benzoxazole periphery entirely removes remaining h5-HT2B activity. Compounds with single digit nM activity, functional antagonism and favorable physicochemical properties endowed with a good pharmacokinetic profile in rats are described which should become valuable tools for exploring the pharmacological role of the SST5 receptor in vivo.
Subject(s)
Benzoxazoles/chemistry , Piperidines/chemistry , Receptors, Somatostatin/antagonists & inhibitors , Animals , Benzoxazoles/chemical synthesis , Benzoxazoles/pharmacokinetics , Crystallography, X-Ray , Male , Molecular Conformation , Piperidines/chemical synthesis , Piperidines/pharmacokinetics , Rats , Rats, Wistar , Receptors, Somatostatin/metabolism , Structure-Activity RelationshipABSTRACT
Design, synthesis, and SAR of novel alpha-alkoxy-beta-arylpropionic acids as potent and balanced PPARalphagamma coagonists are described. One representative thereof, Aleglitazar ((S)-2Aa), was chosen for clinical development. Its X-ray structure in complex with both receptors as well as its high efficacy in animal models of T2D and dyslipidemia are also presented.
Subject(s)
Diabetes Mellitus, Type 2/drug therapy , Oxazoles/chemical synthesis , Oxazoles/pharmacology , PPAR alpha/agonists , PPAR gamma/agonists , Thiophenes/chemical synthesis , Thiophenes/pharmacology , Animals , Chemistry, Pharmaceutical/methods , Crystallography, X-Ray/methods , Drug Design , Dyslipidemias/drug therapy , Humans , Inhibitory Concentration 50 , Ligands , Models, Chemical , Molecular Structure , Receptors, Cytoplasmic and Nuclear/metabolismABSTRACT
An X-ray-guided design approach led to the identification of a novel, balanced class of alpha-ethoxy-phenylpropionic acid-derived dual PPARalpha/gamma agonists. The series shows a wide range of PPARalpha/gamma ratios within a rather narrow structural space. Advanced compounds possess favorable physicochemical and pharmacokinetic profiles and show a high efficacy in T2D and dyslipidemia animal models.
Subject(s)
Hypolipidemic Agents/chemistry , PPAR alpha/agonists , PPAR gamma/agonists , Phenylpropionates/chemistry , Animals , Computer Simulation , Crystallography, X-Ray , Diabetes Mellitus, Type 2/drug therapy , Drug Design , Humans , Hypolipidemic Agents/chemical synthesis , Hypolipidemic Agents/pharmacokinetics , Mice , PPAR alpha/metabolism , PPAR gamma/metabolism , Phenylpropionates/chemical synthesis , Phenylpropionates/pharmacokinetics , Rats , Stereoisomerism , Structure-Activity RelationshipABSTRACT
In the quest for novel PPARalpha/gamma co-agonists as putative drugs for the treatment of type 2 diabetes and dyslipidemia, we have used a structure-based design approach to identify propionic acids with a 1,5-disubstituted indole scaffold as potent PPARalpha/gamma activators. Compounds 13, 24, and 28 are examples of submicromolar dual agonists with different alpha/gamma EC50 ratios that are selective against the delta-isoform. Analysis of the X-ray complex structure of PPARgamma with the indole propionic acid 13 provides a rationalization for some of the observed SAR.
