ABSTRACT
A series of trans-2-aryl-cyclopropylamine derived compounds were synthesized and evaluated their biological activities against DPP-IV. The structure-activity relationships (SAR) led to the discovery of novel series of DPP-IV inhibitors, having IC(50) values of <100 nM with excellent selectivity over the closely related enzymes, DPP8, DPP-II and FAP. The studies identified a potent and selective DPP-IV inhibitor 24b, which exhibited the ability to both significantly inhibit plasma DPP-IV activity in rats and improve glucose tolerance in lean mice and diet induced obese mice.
Subject(s)
Cyclopropanes/chemistry , Cyclopropanes/pharmacology , Dipeptidyl-Peptidase IV Inhibitors , Protease Inhibitors/chemistry , Protease Inhibitors/pharmacology , Animals , Dipeptidyl Peptidase 4/blood , Glucose Tolerance Test , Magnetic Resonance Spectroscopy , Mice , Rats , Rats, Wistar , Spectrometry, Mass, Electrospray Ionization , Structure-Activity RelationshipABSTRACT
Reactions of camphor-, and camphene-derived formyl [2.2.1]bicyclic carbinols with Grignard and organolithium reagents afford the corresponding regio- and stereospecific alkyl/aryl [3.2.1]bicyclic diols. Some of these bicyclic diols have been treated with lead tetraacetate to provide new chiral cyclopentane derivatives. A plausible mechanism of the ring expansion-alkylation reaction is proposed.
ABSTRACT
Based on the structures of NVP-DPP728 (1) and NVP-LAF237 (Vildagliptin, 2), three series of DPP-IV inhibitors were synthesized by linking substituted anilines, benzylamines, and phenylethylamines to (2S)-cyanopyrrolidine through a linker. More than 20 compounds were evaluated for their in vitro DPP-IV inhibition and selectivity profile over DPP-II, DPP8, and FAP enzymes. Selected compounds 5f and 7i showed in vivo plasma DPP-IV inhibition and inhibited glucose excursion in OGTT after oral administration in Wistar rats. Compound 5f (DPP-IV IC50 = 116 nM) has the potential for development as antidiabetic agent.
Subject(s)
Adenosine Deaminase Inhibitors , Amides/pharmacology , Diabetes Mellitus, Type 2/drug therapy , Dipeptidyl-Peptidase IV Inhibitors , Glycoproteins/antagonists & inhibitors , Adamantane/analogs & derivatives , Amides/chemical synthesis , Aniline Compounds , Animals , Benzylamines , Dipeptidyl Peptidase 4 , Inhibitory Concentration 50 , Nitriles , Phenethylamines , Pyrrolidines , Rats , Rats, Wistar , Structure-Activity Relationship , VildagliptinABSTRACT
A series of substituted pyrrolidine-2,4-dicarboxylic acid amides were synthesized as potential antidiabetic agents, and many of them showed good in vitro DPP-IV inhibition (IC50 = 2-250 nM) with selectivity over DPP-II, DPP8, and FAP enzymes. Selected compounds 8c and 11a showed in vivo plasma DPP-IV inhibition after oral administration in Wistar rats.
Subject(s)
Amides/chemistry , Amides/pharmacology , Dicarboxylic Acids/chemistry , Dipeptidyl Peptidase 4/metabolism , Protease Inhibitors/chemical synthesis , Protease Inhibitors/pharmacology , Pyrrolidines/chemistry , Amides/chemical synthesis , Animals , Drug Design , Molecular Structure , Protease Inhibitors/chemistry , Rats , Rats, Wistar , Structure-Activity RelationshipABSTRACT
Dipeptidyl peptidase IV (DPP-IV) inhibitors are expected to become a new type of antidiabetic drugs. Most known DPP-IV inhibitors often resemble the dipeptide cleavage products, with a proline mimic at the P1 site. As off-target inhibitions of DPP8 and/or DPP9 have shown profound toxicities in the in vivo studies, it is important to develop selective DPP-IV inhibitors for clinical usage. To achieve this, a new class of 2-[3-[[2-[(2S)-2-cyano-1-pyrrolidinyl]-2-oxoethyl]amino]-1-oxopropyl]-based DPP-IV inhibitors was synthesized. SAR studies resulted in a number of DPP-IV inhibitors, having IC(50) values of <50 nM with excellent selectivity over both DPP8 (IC(50) > 100 microM) and DPP-II (IC(50) > 30 microM). Compound 21a suppressed the blood glucose elevation after an oral glucose challenge in Wistar rats and also inhibited plasma DPP-IV activity for up to 4 h in BALB/c mice. The results show that compound 21a possesses in vitro and in vivo activities comparable to those of NVP-LAF237 (4), which is in clinical development.
Subject(s)
Dipeptidyl Peptidase 4/drug effects , Enzyme Inhibitors/pharmacology , Isoquinolines/pharmacology , Pyrrolidinones/pharmacology , Administration, Oral , Animals , Blood Glucose/drug effects , Dipeptidases/antagonists & inhibitors , Dipeptidyl Peptidase 4/blood , Dipeptidyl-Peptidases and Tripeptidyl-Peptidases/antagonists & inhibitors , Drug Evaluation, Preclinical , Drug Tolerance , Enzyme Inhibitors/chemical synthesis , Glucose/administration & dosage , Glucose/antagonists & inhibitors , Humans , In Vitro Techniques , Isoquinolines/chemical synthesis , Male , Mice , Mice, Inbred BALB C , Molecular Conformation , Pyrrolidinones/chemical synthesis , Rats , Rats, Wistar , Structure-Activity Relationship , Time FactorsABSTRACT
To find potent and selective inhibitors of dipeptidyl peptidase IV (DPP-IV), we synthesized a series of 2-cyanopyrrolidine with P2-site 4-substituted glutamic acid derivatives and tested their activities against DPP-IV, DPP8, and DPP-II. Analogues that incorporated a bulky substituent at the first carbon position of benzylamine or isoquinoline showed over 30-fold selectivity for DPP-IV over both DPP8 and DPP-II. From structure-activity relationship studies, we speculate that the S2 site of DPP8 might be similar to that of DPP-IV, while DPP-IV inhibitor with N-substituted glycine in the P2 site and/or with a moiety involving in hydrophobic interaction with the side chain of Phe357 might provide a better selectivity for DPP-IV over DPP8.
Subject(s)
Dipeptidyl-Peptidases and Tripeptidyl-Peptidases/antagonists & inhibitors , Enzyme Inhibitors/chemical synthesis , Glutamic Acid/analogs & derivatives , Adenosine Deaminase Inhibitors , Binding Sites , Dipeptidases/antagonists & inhibitors , Dipeptidyl Peptidase 4 , Enzyme Inhibitors/pharmacology , Glutamic Acid/chemical synthesis , Glutamic Acid/pharmacology , Glycoproteins/antagonists & inhibitors , Humans , Hydrophobic and Hydrophilic Interactions , Inhibitory Concentration 50 , Models, Molecular , Protein Binding , Pyrrolidines/chemical synthesis , Pyrrolidines/pharmacology , Structure-Activity RelationshipABSTRACT
DPP8 is a prolyl dipeptidase homologous to DPP-IV, which is a drug target for Type II diabetes. The biological function of DPP8 is not known. To identify potent and selective chemical compounds against DPP8, we have synthesized a series of isoquinoline and isoindoline derivatives and have tested their inhibitory activity against DPP8, DPP-IV and DPP-II. Isoindoline derivatives were found to be more potent DPP8 inhibitors than isoquinoline derivatives. Isoindoline with a 1-(4,4'-difluor-benzhydryl)-piperazine group at the P2 site was observed to be a very potent DPP8 inhibitor, having an IC(50) value of 14nM with at least a 2500-fold selectivity over either DPP-IV or DPP-II. From SAR results, we speculate that the S1 site of DPP8 may be larger than that of DPP-IV, which would allow the accommodation of larger C-terminal residues, such as isoquinoline or isoindoline.
