ABSTRACT
A novel series of arylindenopyrimidines were identified as A(2A) and A(1) receptor antagonists. The series was optimized for in vitro activity by substituting the 8- and 9-positions with methylene amine substituents. The compounds show excellent activity in mouse models of Parkinson's disease when dosed orally.
Subject(s)
Adenosine A1 Receptor Antagonists , Adenosine A2 Receptor Antagonists , Amines/chemistry , Neurotransmitter Agents/chemistry , Pyrimidines/chemistry , Amines/chemical synthesis , Amines/therapeutic use , Animals , Catalepsy/drug therapy , Disease Models, Animal , Mice , Neurotransmitter Agents/chemical synthesis , Neurotransmitter Agents/therapeutic use , Pyrimidines/chemical synthesis , Pyrimidines/therapeutic use , Receptor, Adenosine A1/metabolism , Receptor, Adenosine A2A/metabolism , Structure-Activity RelationshipABSTRACT
Two reactive metabolites were identified in vivo for the dual A(2A)/A(1) receptor antagonist 1. Two strategies were implemented to successfully mitigate the metabolic liabilities associated with 1. Optimization of the arylindenopyrimidines led to a number of amide, ether, and amino analogs having comparable in vitro and in vivo activity.
Subject(s)
Adenosine A1 Receptor Antagonists , Adenosine A2 Receptor Antagonists , Neurotransmitter Agents/chemistry , Pyrimidines/chemistry , Animals , Catalepsy/drug therapy , Disease Models, Animal , Mice , Neurotransmitter Agents/chemical synthesis , Neurotransmitter Agents/therapeutic use , Pyrimidines/chemical synthesis , Pyrimidines/therapeutic use , Receptor, Adenosine A1/metabolism , Receptor, Adenosine A2A/metabolism , Structure-Activity RelationshipABSTRACT
The p38 MAP kinase is thought to be involved in a variety of inflammatory and immunological disorders such as rheumatoid arthritis. The pyridinylimidazole class of compounds was the first to potently inhibit this kinase. Since the original reports of their efficacy, they have become the most widely studied series of inhibitors of this kinase. This framework has served as a starting point for further synthetic work and several compounds have entered clinical trials. These compounds have also been utilized to elucidate the role of p38 kinase in the immune system, and more recently have been used to examine the role of this kinase in central nervous system disorders.
Subject(s)
Enzyme Inhibitors/chemistry , Enzyme Inhibitors/pharmacology , Imidazoles/chemistry , Imidazoles/pharmacology , Mitogen-Activated Protein Kinases/antagonists & inhibitors , Pyridines/chemistry , Pyridines/pharmacology , Animals , Antirheumatic Agents/chemistry , Antirheumatic Agents/pharmacology , Arthritis, Experimental/drug therapy , Drug Design , Humans , Indoles/chemistry , Indoles/pharmacology , Mitogen-Activated Protein Kinases/immunology , Mitogen-Activated Protein Kinases/metabolism , Oxazoles/chemistry , Oxazoles/pharmacology , Structure-Activity Relationship , Thiazoles/chemistry , Thiazoles/pharmacology , Tumor Cells, Cultured/drug effects , p38 Mitogen-Activated Protein KinasesABSTRACT
The in vivo characterization of a dual adenosine A(2A)/A(1) receptor antagonist in several animal models of Parkinson's disease is described. Discovery and scale-up syntheses of compound 1 are described in detail, highlighting optimization steps that increased the overall yield of 1 from 10.0% to 30.5%. Compound 1 is a potent A(2A)/A(1) receptor antagonist in vitro (A(2A) K(i) = 4.1 nM; A(1) K(i) = 17.0 nM) that has excellent activity, after oral administration, across a number of animal models of Parkinson's disease including mouse and rat models of haloperidol-induced catalepsy, mouse model of reserpine-induced akinesia, rat 6-hydroxydopamine (6-OHDA) lesion model of drug-induced rotation, and MPTP-treated non-human primate model.
Subject(s)
Adenosine A1 Receptor Antagonists/chemical synthesis , Adenosine A2 Receptor Antagonists/chemical synthesis , Antiparkinson Agents/chemical synthesis , Indenes/chemical synthesis , Parkinson Disease/metabolism , Pyrimidines/chemical synthesis , Receptor, Adenosine A2A/physiology , Adenosine A1 Receptor Antagonists/pharmacokinetics , Adenosine A1 Receptor Antagonists/pharmacology , Adenosine A2 Receptor Antagonists/pharmacokinetics , Adenosine A2 Receptor Antagonists/pharmacology , Administration, Oral , Animals , Antiparkinson Agents/pharmacokinetics , Antiparkinson Agents/pharmacology , Callithrix , Disease Models, Animal , Female , Indenes/pharmacokinetics , Indenes/pharmacology , Macaca fascicularis , Male , Mice , Mice, Inbred BALB C , Pyrimidines/pharmacokinetics , Pyrimidines/pharmacology , Rats , Rats, Sprague-DawleyABSTRACT
Methylisocyanoacetate undergoes a 2 + 3 cycloaddition with alpha,beta-unsaturated nitriles to provide a regioselective synthesis of 2-substituted 3,4-diaryl pyrroles. The ease of preparation of alpha,beta-unsaturated nitriles allows the rapid synthesis of pyrroles with varied substituents. Using this method, a key intermediate (1) for the synthesis of the marine natural products lukianol A, lamellarin O, and lamellarin Q was prepared in two steps. A total synthesis of ningalin B (11) was also accomplished utilizing this methodology.