ABSTRACT
The synthesis and SAR of aminomethyl-substituted imidazolopyrimidine DPP4 inhibitors bearing varied pendant aryl groups is described. Compound 1, which exists as a separable mixture of non-interconvertible atropisomers was used as the starting point for investigation. The effects of substituent pattern and type as well as stereochemical effects on inhibitor potency are discussed.
Subject(s)
Dipeptidyl-Peptidase IV Inhibitors/chemical synthesis , Dipeptidyl-Peptidase IV Inhibitors/pharmacology , Imidazoles/chemical synthesis , Imidazoles/pharmacology , Pyrimidines/chemical synthesis , Pyrimidines/pharmacology , Catalytic Domain , Dipeptidases/antagonists & inhibitors , Dipeptidyl-Peptidase IV Inhibitors/chemistry , Dipeptidyl-Peptidases and Tripeptidyl-Peptidases/antagonists & inhibitors , Indicators and Reagents , Isomerism , Kinetics , Models, Molecular , Solvents , Structure-Activity RelationshipABSTRACT
A novel selective androgen receptor modulator (SARM) scaffold was discovered as a byproduct obtained during synthesis of our earlier series of imidazolidin-2-ones. The resulting oxazolidin-2-imines are among the most potent SARMs known, with many analogues exhibiting sub-nM in vitro potency in binding and functional assays. Despite the potential for hydrolytic instability at gut pH, compounds of the present class showed good oral bioavailability and were highly active in a standard rodent pharmacological model.
Subject(s)
Androgens , Muscles/drug effects , Muscles/metabolism , Oxazoles/chemistry , Oxazoles/pharmacology , Animals , Crystallography, X-Ray , Humans , Hydrogen-Ion Concentration , Male , Models, Molecular , Molecular Conformation , Prostate/drug effects , Prostate/metabolism , Rats , Substrate SpecificityABSTRACT
Several series of pyridine amides were identified as selective and potent 11beta-HSD1 inhibitors. The most potent inhibitors feature 2,6- or 3,5-disubstitution on the pyridine core. Various linkers (CH(2)SO(2), CH(2)S, CH(2)O, S, O, N, bond) between the distal aryl and central pyridyl groups are tolerated, and lipophilic amide groups are generally favored. On the distal aryl group, a number of substitutions are well tolerated. A crystal structure was obtained for a complex between 11beta-HSD1 and the most potent inhibitor in this series.
Subject(s)
11-beta-Hydroxysteroid Dehydrogenase Type 1/antagonists & inhibitors , Amides/chemical synthesis , Amides/pharmacology , Pyridines/chemical synthesis , Pyridines/pharmacology , Amides/chemistry , Combinatorial Chemistry Techniques , Crystallography, X-Ray , Drug Design , Humans , Inhibitory Concentration 50 , Molecular Conformation , Molecular Structure , Pyridines/chemistry , Structure-Activity RelationshipABSTRACT
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
Dipeptidyl peptidase IV (DPP4) is a multifunctional type II transmembrane serine peptidase which regulates various physiological processes, most notably plasma glucose homeostasis by cleaving peptide hormones glucagon-like peptide-1 and glucose-dependent insulinotropic polypeptide. Inhibition of DPP4 is a potentially valuable therapy for type 2 diabetes. Synthesis and structure-activity relationships of a series of substituted diprolyl nitriles are described, leading to the identification of compound 1 with a measured DPP4 K(i) of 3.6 nM.
Subject(s)
Dipeptidyl Peptidase 4/metabolism , Nitriles/pharmacology , Protease Inhibitors/pharmacology , Binding Sites , Cyclization , Dipeptidyl Peptidase 4/chemistry , Models, Molecular , Molecular Structure , Nitriles/chemistry , Protease Inhibitors/chemistry , Protein Structure, TertiaryABSTRACT
Efforts to further elucidate structure-activity relationships (SAR) within our previously disclosed series of beta-quaternary amino acid linked l-cis-4,5-methanoprolinenitrile dipeptidyl peptidase IV (DPP-IV) inhibitors led to the investigation of vinyl substitution at the beta-position of alpha-cycloalkyl-substituted glycines. Despite poor systemic exposure, vinyl-substituted compounds showed extended duration of action in acute rat ex vivo plasma DPP-IV inhibition models. Oxygenated putative metabolites were prepared and were shown to exhibit the potency and extended duration of action of their precursors in efficacy models measuring glucose clearance in Zucker(fa/fa) rats. Extension of this approach to adamantylglycine-derived inhibitors led to the discovery of highly potent inhibitors, including hydroxyadamantyl compound BMS-477118 (saxagliptin), a highly efficacious, stable, and long-acting DPP-IV inhibitor, which is currently undergoing clinical trials for treatment of type 2 diabetes.
Subject(s)
Adamantane/analogs & derivatives , Adamantane/chemical synthesis , Diabetes Mellitus, Type 2/drug therapy , Dipeptides/chemical synthesis , Dipeptidyl Peptidase 4/metabolism , Glycine/analogs & derivatives , Glycine/chemical synthesis , Hypoglycemic Agents/chemical synthesis , Protease Inhibitors/chemical synthesis , Adamantane/pharmacology , Animals , Biological Availability , Blood Glucose/analysis , Diabetes Mellitus, Type 2/physiopathology , Dipeptides/pharmacology , Glucose Tolerance Test , Glycine/pharmacology , Humans , Hypoglycemic Agents/pharmacology , In Vitro Techniques , Insulin/blood , Male , Mice , Mice, Obese , Microsomes, Liver/metabolism , Nitriles/chemical synthesis , Nitriles/pharmacology , Proline/analogs & derivatives , Proline/chemical synthesis , Proline/pharmacology , Protease Inhibitors/pharmacology , Rats , Rats, Zucker , Stereoisomerism , Structure-Activity RelationshipABSTRACT
A series of methanoprolinenitrile-containing dipeptide mimetics were synthesized and assayed as inhibitors of the N-terminal sequence-specific serine protease dipeptidyl peptidase IV (DPP-IV). The catalytic action of DPP-IV is the principle means of degradation of glucagon-like peptide-1, a key mediator of glucose-stimulated insulin secretion, and DPP-IV inhibition shows clinical benefit as a novel mechanism for treatment of type 2 diabetes. However, many of the reversible inhibitors to date suffer from chemical instability stemming from an amine to nitrile intramolecular cyclization. Installation of a cyclopropyl moiety at either the 3,4- or 4,5-position of traditional 2-cyanopyrrolidide proline mimetics led to compounds with potent inhibitory activity against the enzyme. Additionally, cis-4,5-methanoprolinenitriles with beta-branching in the N-terminal amino acid provided enhanced chemical stability and high inhibitory potency. This class of inhibitors also exhibited the ability to suppress prandial glucose elevations after an oral glucose challenge in male Zucker rats.