ABSTRACT
A novel series of benzyl substituted thieno[2,3-d]pyrimidines were identified as potent A2A receptor antagonists. Several five- and six-membered heterocyclic replacements for the optimized methylfuran were explored. Select compounds effectively reverse catalepsy in mice when dosed orally.
Subject(s)
Adenosine A2 Receptor Antagonists/chemistry , Pyrimidines/chemistry , Receptor, Adenosine A2A/metabolism , Adenosine A2 Receptor Antagonists/pharmacokinetics , Adenosine A2 Receptor Antagonists/therapeutic use , Animals , Brain/metabolism , Catalepsy/drug therapy , Half-Life , Humans , Kinetics , Mice , Protein Binding , Pyrimidines/pharmacokinetics , Pyrimidines/therapeutic use , Rats , Receptor, Adenosine A2A/chemistryABSTRACT
The design and characterization of two, dual adenosine A(2A)/A(1) receptor antagonists in several animal models of Parkinson's disease is described. Compound 1 was previously reported as a potential treatment for Parkinson's disease. Further characterization of 1 revealed that it was metabolized to reactive intermediates that caused the genotoxicity of 1 in the Ames and mouse lymphoma L51784 assays. The identification of the metabolites enabled the preparation of two optimized compounds 13 and 14 that were devoid of the metabolic liabilities associated with 1. Compounds 13 and 14 are potent dual A(2A)/A(1) receptor antagonists that have 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 and rat models of reserpine-induced akinesia, and the rat 6-hydroxydopamine (6-OHDA) lesion model of drug-induced rotation.
Subject(s)
Adenosine A1 Receptor Antagonists/chemical synthesis , Adenosine A2 Receptor Antagonists/chemical synthesis , Indenes/chemical synthesis , Parkinsonian Disorders/drug therapy , Pyrimidines/chemical synthesis , Receptor, Adenosine A2A/metabolism , Adenosine A1 Receptor Antagonists/pharmacokinetics , Adenosine A1 Receptor Antagonists/pharmacology , Adenosine A2 Receptor Antagonists/pharmacokinetics , Adenosine A2 Receptor Antagonists/pharmacology , Administration, Oral , Animals , Drug Design , Female , Indenes/pharmacokinetics , Indenes/pharmacology , Macaca fascicularis , Male , Mice , Mice, Inbred BALB C , Parkinsonian Disorders/chemically induced , Pyrimidines/pharmacokinetics , Pyrimidines/pharmacology , Rats , Rats, Sprague-Dawley , Structure-Activity RelationshipABSTRACT
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
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
A series of novel carboxylic acid-based alpha-sulfone MMP inhibitors have been synthesized and the in vitro enzyme SAR is discussed. A potential binding mode in the active site of the MMP-9 homology model was highlighted. These compounds are potent MMP-9 inhibitors and are selective over MMP-1.
