ABSTRACT
Sugars and simplified oligosaccharide "mimics" can be joined with protein fragments at pre-defined sites using reliable chemical reactions such as thiol alkylation and Cu(I) catalysed azide/acetylene ligation (click chemistry). These fragments have the potential to be assembled into neoglycoprotein therapeutics using native chemical ligation.
Subject(s)
Glycopeptides/chemistry , Glycoproteins/chemistry , Nitrogen/chemistry , Sulfur/chemistry , Amino Acid Sequence , Biomimetic Materials/chemical synthesis , Biomimetic Materials/chemistry , Models, Molecular , Molecular Sequence Data , Oligosaccharides/chemistry , Protein Conformation , Substrate SpecificityABSTRACT
Antagonists of the human A(2A) receptor have been reported to have potential therapeutic benefit in the alleviation of the symptoms associated with neurodegenerative movement disorders such as Parkinson's disease. As part of our efforts to discover potent and selective antagonists of this receptor, we herein describe the detailed optimization and structure-activity relationships of a series of pyrimidine-4-carboxamides. These optimized derivatives display desirable physiochemical and pharmacokinetic profiles, which have led to promising oral activity in clinically relevant models of Parkinson's disease.
Subject(s)
Adenosine A2 Receptor Antagonists , Parkinson Disease/drug therapy , Pyrimidines/chemistry , Pyrimidines/pharmacology , Receptor, Adenosine A2A/metabolism , Animals , Humans , Locomotion/drug effects , Mice , Protein Binding , Pyrimidines/pharmacokinetics , Pyrimidines/therapeutic use , Structure-Activity RelationshipABSTRACT
Antagonism of the human A(2A) receptor has been implicated as a point of therapeutic intervention in the alleviation of the symptoms associated with Parkinson's disease. This is thought to occur, at least in part, by increasing the sensitivity of the dopaminergic neurons to the residual, depleted levels of striatal dopamine. We herein describe a novel series of functionalized triazolo[4,5-d]pyrimidine derivatives that display functional antagonism of the A(2A) receptor. Optimization of these compounds has resulted in improvements in potency, selectivity, and the pharmacokinetic properties of key derivatives. These efforts have led to the discovery of 60 (V2006/BIIB014), which demonstrates strong oral activity in commonly used models of Parkinson's disease. Furthermore, this derivative has shown excellent preclinical pharmacokinetics and has successfully completed phase I clinical studies. This compound is presently undergoing further clinical evaluation in collaboration with Biogen Idec.
Subject(s)
Adenosine A2 Receptor Antagonists , Azoles/chemical synthesis , Azoles/pharmacology , Drug Design , Pyrimidines/chemical synthesis , Pyrimidines/pharmacology , Amines/chemistry , Animals , Azoles/chemistry , Azoles/therapeutic use , Drug Evaluation, Preclinical , Gait Disorders, Neurologic/chemically induced , Gait Disorders, Neurologic/drug therapy , Haloperidol/pharmacology , Humans , Mice , Molecular Structure , Pyrimidines/chemistry , Pyrimidines/therapeutic use , Rats , Receptor, Adenosine A2A/classification , Receptor, Adenosine A2A/metabolism , Structure-Activity RelationshipABSTRACT
A protocol for the construction of poly-oxazoles with consecutive 2,4'-linkages is described, and has afforded an efficient route to a penta-oxazole which demarcates a route to telomestatin and related macrocyclic poly-oxazole systems.
