ABSTRACT
The 5-HT2C receptor has been implicated as a critical regulator of appetite. Small molecule activation of the 5-HT2C receptor has been shown to affect food intake and regulate body weight gain in rodent models and more recently in human clinical trials. Therefore, 5-HT2C is a well validated target for anti-obesity therapy. The synthesis and structure-activity relationships of a series of novel tetrahydropyrazinoisoquinolinone 5-HT2C receptor agonists are presented. Several members of this series were identified as potent 5-HT2C receptor agonists with high functional selectivity against the 5-HT2A and 5-HT2B receptors and reduced food intake in an acute rat feeding model upon oral dosing.
Subject(s)
Isoquinolines/pharmacology , Pyrazines/pharmacology , Receptor, Serotonin, 5-HT2C/metabolism , Animals , Crystallography, X-Ray , Dose-Response Relationship, Drug , Eating/drug effects , Humans , Isoquinolines/chemical synthesis , Isoquinolines/chemistry , Models, Molecular , Molecular Structure , Pyrazines/chemical synthesis , Pyrazines/chemistry , Rats , Structure-Activity RelationshipABSTRACT
Synthesis and structure-activity relationship of a series of substituted piperidinyl glycine 2-cyano-4,5-methano pyrroline DPP-IV inhibitors are described. Improvement of the inhibitory activity and chemical stability of this series of compounds was respectively achieved by the introduction of bulky groups at the 4-position and 1-position of the piperidinyl glycine, leading to a series of potent and stable DPP-IV inhibitors.
Subject(s)
Dipeptidyl Peptidase 4/chemistry , Dipeptidyl-Peptidase IV Inhibitors/chemistry , Piperidines/chemistry , Pyrrolidines/chemistry , Dipeptidyl Peptidase 4/metabolism , Dipeptidyl-Peptidase IV Inhibitors/chemical synthesis , Dipeptidyl-Peptidase IV Inhibitors/metabolism , Humans , Hydrogen-Ion Concentration , Protein Binding , Pyrrolidines/chemical synthesis , Pyrrolidines/metabolism , Structure-Activity Relationship , TemperatureABSTRACT
The synthesis and structure-activity relationships of novel dipeptidyl peptidase IV inhibitors replacing the classical cyanopyrrolidine P1 group with other small nitrogen heterocycles are described. A unique potency enhancement was achieved with beta-branched natural and unnatural amino acids, particularly adamantylglycines, linked to a (2S,3R)-2,3-methanopyrrolidine based scaffold.
Subject(s)
Dipeptides/chemistry , Dipeptidyl-Peptidase IV Inhibitors , Dipeptidyl-Peptidase IV Inhibitors/chemistry , Dipeptides/pharmacology , Dipeptidyl-Peptidase IV Inhibitors/pharmacology , Drug Evaluation, Preclinical , Humans , Nitriles/chemistry , Nitriles/pharmacology , Structure-Activity RelationshipABSTRACT
The serine protease tryptase has been associated with a broad range of allergic and inflammatory diseases and, in particular, has been implicated as a critical mediator of asthma. The inhibition of tryptase therefore has the potential to be a valuable therapy for asthma. The synthesis, employing solution phase parallel methods, and SAR of a series of novel 2-azepanone tryptase inhibitors are presented. A member of this series, 8t, was identified as a potent inhibitor of human tryptase (IC(50)=38 nM) with selectivity >/=330-fold versus related serine proteases (trypsin, plasmin, uPA, tPA, APC, alpha-thrombin, and FXa) [corrected].
Subject(s)
Azepines/chemical synthesis , Serine Endopeptidases/metabolism , Serine Proteinase Inhibitors/chemical synthesis , Azepines/pharmacology , Humans , Serine Proteinase Inhibitors/pharmacology , TryptasesABSTRACT
In our continuing efforts to identify small molecule vitronectin receptor antagonists, we have discovered a series of phenylbutyrate derivatives, exemplified by 16, which have good potency and excellent oral bioavailability (approximately 100% in rats). This new series is derived conceptually from opening of the seven-membered ring of SB-265123.
Subject(s)
Integrin alphaVbeta3/antagonists & inhibitors , Phenylbutyrates/pharmacology , Phenylbutyrates/pharmacokinetics , Acetates/chemistry , Administration, Oral , Aminopyridines/chemistry , Animals , Biological Availability , Cell Adhesion/drug effects , Cell Line , Half-Life , Humans , Phenylbutyrates/chemistry , RatsABSTRACT
Screening of our internal compound collection for inhibitors of the transforming growth factor beta1 (TGF-beta1) type I receptor (ALK5) identified several hits. Optimization of the dihydropyrroloimidazole hit 2 by introduction of a 2-pyridine and 3,4-methylenedioxyphenyl group gave 7, a selective ALK5 inhibitor. With this information, optimization of the triarylimidazole hit 8 gave the selective inhibitor 14, which inhibits TGF-beta1-induced fibronectin mRNA formation while displaying no measurable cytotoxicity in the 48 h XTT assay.
