ABSTRACT
Despite investment in programs to manage the development of resistance to existing agents, this continues to drive the need for discovery of novel antiparasitic agents for veterinary medicine. Historically, antiparasitic drug discovery was driven by empirical screening, but technological advances have lead to an increased focus on mechanism-based approaches to drug discovery and this is projected to increase as our capabilities advance to improve both the throughput of assays and the quality of data generated. Investment in the development of combination products with novel agents is increasing and, despite regulatory hurdles in some regions, efforts to globally harmonize regulations will aid in delivering safe, efficacious drugs to help in resistance management and integrated parasite control programs.
Subject(s)
Antiparasitic Agents/chemistry , Drug Discovery/trends , Veterinary Drugs/chemistry , Aminoacetonitrile/chemistry , Aminoacetonitrile/pharmacokinetics , Animals , Antiparasitic Agents/pharmacokinetics , Drug Combinations , Macrolides/chemistry , Macrolides/pharmacokinetics , Oxazines/chemistry , Oxazines/pharmacokinetics , Semicarbazones/chemistry , Semicarbazones/pharmacokinetics , Veterinary Drugs/pharmacokineticsABSTRACT
We describe three novel regioisomeric series of aryl naphthyridine analogs, which are potent antagonists of the Class III GPCR mGlu5 receptor. The synthesis and in vitro and in vivo pharmacological activities of these analogs are discussed.
Subject(s)
Naphthyridines/chemical synthesis , Naphthyridines/pharmacology , Receptors, Metabotropic Glutamate/antagonists & inhibitors , Animals , CHO Cells , Cricetinae , Cricetulus , Rats , Receptor, Metabotropic Glutamate 5 , Receptors, Metabotropic Glutamate/physiology , Stereoisomerism , Structure-Activity RelationshipABSTRACT
A novel series of potent 2-aryl pyrido[2,3-d]pyrimidine mGlu5 receptor antagonists are described. The synthesis and pharmacological activities of these analogs are discussed.
Subject(s)
Excitatory Amino Acid Antagonists/chemical synthesis , Excitatory Amino Acid Antagonists/pharmacology , Pyrimidines/chemical synthesis , Pyrimidines/pharmacology , Receptors, Metabotropic Glutamate/antagonists & inhibitors , Animals , CHO Cells , Calcium/metabolism , Cricetinae , Cricetulus , Cyclooxygenase 2 Inhibitors/therapeutic use , Indicators and Reagents , Joints/pathology , Lactones/therapeutic use , Osteoarthritis/chemically induced , Osteoarthritis/drug therapy , Osteoarthritis/pathology , Pyridines/chemistry , Pyridines/pharmacology , Rats , Receptor, Metabotropic Glutamate 5 , Structure-Activity Relationship , Sulfones/therapeutic useABSTRACT
Rational replacement of the alkyne linker of mGluR5 antagonist MPEP gave 7-arylquinolines. SAR optimization gave an orally active compound with high affinity for the MPEP binding site.
Subject(s)
Drug Design , Excitatory Amino Acid Antagonists/chemistry , Excitatory Amino Acid Antagonists/pharmacology , Quinolines/chemistry , Quinolines/pharmacology , Receptors, Metabotropic Glutamate/antagonists & inhibitors , Models, Molecular , Molecular Structure , Pyridines/chemistry , Pyridines/pharmacology , Receptor, Metabotropic Glutamate 5 , Structure-Activity RelationshipABSTRACT
We describe a series of 1,2,4-oxadiazoles, which are potent antagonists of the integrin alpha(v)beta3 and, in addition, show selectivity relative to the other beta3 integrin alpha(IIb)beta3. In whole cells, the majority of these analogs also demonstrated modest selectivity against other alpha(v) integrins such as alpha(v)beta1 and alpha(v)beta6.
Subject(s)
Butyrates/chemical synthesis , Butyrates/pharmacology , Integrin alphaVbeta3/antagonists & inhibitors , Oxadiazoles/chemical synthesis , Oxadiazoles/pharmacology , Antigens, Neoplasm , Butyrates/chemistry , Cell Line , Humans , Integrins/antagonists & inhibitors , Molecular Structure , Oxadiazoles/chemistry , Receptors, Vitronectin/antagonists & inhibitors , Structure-Activity RelationshipABSTRACT
We describe a series of 2,5 thiazole containing compounds, which are potent antagonists of the integrin alpha(v)beta3 and show selectivity relative to the other integrins, such as alpha(IIb)beta3 and alpha(v)beta6. These analogs were demonstrated to have high bioavailability relative to other relative heterocyclic analogs.
Subject(s)
Butyrates/chemical synthesis , Butyrates/pharmacokinetics , Integrin alphaVbeta3/antagonists & inhibitors , Thiazoles/chemical synthesis , Thiazoles/pharmacokinetics , Administration, Oral , Animals , Antigens, Neoplasm , Biological Availability , Butyrates/administration & dosage , Dogs , Drug Evaluation, Preclinical , Haplorhini , Integrins/antagonists & inhibitors , Molecular Structure , Platelet Glycoprotein GPIIb-IIIa Complex/antagonists & inhibitors , Rats , Structure-Activity Relationship , Thiazoles/administration & dosageABSTRACT
[reaction: see text] The total synthesis of (+)-sparteine was accomplished from 2,5-norbornadione in 15 steps and 15.7% overall yield. The key steps were two ring-expansion reactions, one involving an intramolecular Schmidt reaction and one using a novel variant of the photo-Beckmann rearrangement.