ABSTRACT
We describe structure-activity studies leading to the discovery of 2-arylbenzoxazole 3, the first in a series to raise serum high-density lipoprotein cholesterol levels in transgenic mice. Replacement of the 4-piperidinyloxy moiety with piperazinyl provided a more synthetically tractable lead, which upon optimization resulted in compound 4, an excellent inhibitor of cholesteryl ester transfer protein function with good pharmacokinetic properties and in vivo efficacy.
Subject(s)
Acetanilides/chemistry , Benzoxazoles/chemistry , Cholesterol Ester Transfer Proteins/antagonists & inhibitors , Cholesterol, HDL/blood , Acetanilides/chemical synthesis , Acetanilides/pharmacokinetics , Animals , Benzoxazoles/chemical synthesis , Benzoxazoles/pharmacokinetics , Cholesterol Ester Transfer Proteins/metabolism , Mice , Mice, Transgenic , Structure-Activity RelationshipABSTRACT
A series of beta-substituted biarylphenylalanine amides were synthesized and evaluated as inhibitors of dipeptidyl peptidase IV (DPP-4) for the treatment of type 2 diabetes. Optimization of the metabolic profile of early analogues led to the discovery of (2S,3S)-3-amino-4-(3,3-difluoropyrrolidin-1-yl)-N,N-dimethyl-4-oxo-2-(4-[1,2,4]triazolo[1,5-a]pyridin-6-ylphenyl)butanamide (6), a potent, orally active DPP-4 inhibitor (IC(50) = 6.3 nM) with excellent selectivity, oral bioavailability in preclinical species, and in vivo efficacy in animal models. Compound 6 was selected for further characterization as a potential new treatment for type 2 diabetes.
Subject(s)
Diabetes Mellitus, Type 2/drug therapy , Dipeptidyl Peptidase 4/metabolism , Hypoglycemic Agents/chemical synthesis , Phenylalanine/analogs & derivatives , Protease Inhibitors/chemical synthesis , Triazoles/chemical synthesis , Administration, Oral , Animals , Biological Availability , Calcium Channels, L-Type/drug effects , Cell Line , Crystallography, X-Ray , Glucose Tolerance Test , Humans , Hypoglycemic Agents/chemistry , Hypoglycemic Agents/pharmacology , In Vitro Techniques , Male , Mice , Mice, Inbred C57BL , Mice, Obese , Microsomes, Liver/drug effects , Microsomes, Liver/metabolism , Models, Molecular , Muscle Proteins/antagonists & inhibitors , Muscle, Skeletal/metabolism , NAV1.5 Voltage-Gated Sodium Channel , Phenylalanine/chemical synthesis , Phenylalanine/chemistry , Phenylalanine/pharmacology , Protease Inhibitors/chemistry , Protease Inhibitors/pharmacology , Rabbits , Sodium Channels , Stereoisomerism , Structure-Activity Relationship , Triazoles/chemistry , Triazoles/pharmacologyABSTRACT
anti-Substituted beta-methylphenylalanine derived amides have been shown to be potent DPP-IV inhibitors exhibiting excellent selectivity over both DPP8 and DPP9. These are among the most potent compounds reported to date lacking an electrophilic trap. The most potent compound among these is 5-oxo-1,2,4-oxadiazole 44, which is a 3 nM DPP-IV inhibitor.
Subject(s)
Dipeptidyl Peptidase 4/drug effects , Phenylalanine/pharmacology , Protease Inhibitors/pharmacology , Phenylalanine/chemistry , Protease Inhibitors/chemistryABSTRACT
The internal transcribed spacer (ITS) regions including the 3'-end of 18S rRNA gene, 5.8S rRNA gene and the 5'-end of the 28S rRNA gene of Rhizopus spp. were amplified by PCR and analyzed by DNASIS program. Length polymorphism of these region ranged from 564 bp in R. oryzae to 789bp in R. stolonifer. The length and sequence of 5.8S was very conserved with 154~155 bp. The sequence of ITS2 was more variable than that of ITS1. The base substitution rates were ranged from 0 to 0.6069 per site, and higher rate was found in R. stolonifer. In general, transition was usually more frequent than transversion. On the basis of sequencing results, four groups were clustered with value of 61.9% similarity; R. oryzae, R. microspores, R. homothallicus, and R. stolonifer groups.
ABSTRACT
VLA-4 (alpha(4)beta(1), very late activating antigen-4), a key cell surface integrin plays an important role in inflammation by promoting leukocyte attachment and extravasation from the vasculature into the peripheral tissues. As such, VLA-4 antagonists may be useful in the treatment, prevention, and suppression of diseases where cell adhesion and migration are important such as asthma, rheumatoid arthritis, and multiple sclerosis. Herein, we report on the discovery, synthesis, and biological evaluation of amidines as small molecule antagonists of VLA-4.
