Potent and selective adenosine A(2A) receptor antagonists: [1,2,4]-triazolo[4,3-c]pyrimidin-3-ones.

Antagonism of the adenosine A(2A) receptor affords a possible treatment of Parkinson's disease. In the course of investigating pyrazolo[4,3-e]-1,2,4-triazolo[1,5-c]pyrimidine A(2A) antagonists, we prepared [1,2,4]-triazolo[4,3-c]pyrimidin-3-ones with potent and selective (vs A(1)) A(2A) antagonist activity. Structure-activity relationships are described for this series.

Preladenant, a selective A(2A) receptor antagonist, is active in primate models of movement disorders.

Parkinson's Disease (PD) and Extrapyramidal Syndrome (EPS) are movement disorders that result from degeneration of the dopaminergic input to the striatum and chronic inhibition of striatal dopamine D(2) receptors by antipsychotics, respectively. Adenosine A(2A) receptors are selectively localized in the basal ganglia, primarily in the striatopallidal ("indirect") pathway, where they appear to operate in concert with D(2) receptors and have been suggested to drive striatopallidal output balance. In cases of dopaminergic hypofunction, A(2A) receptor activation contributes to the overdrive of the indirect pathway. A(2A) receptor antagonists, therefore, have the potential to restore this inhibitor imbalance. Consequently, A(2A) receptor antagonists have therapeutic potential in diseases of dopaminergic hypofunction such as PD and EPS. Targeting the A(2A) receptor may also be a way to avoid the issues associated with direct dopamine agonists. Recently, preladenant was identified as a potent and highly selective A(2A) receptor antagonist, and has produced a significant improvement in motor function in rodent models of PD. Here we investigate the effects of preladenant in two primate movement disorder models. In MPTP-treated cynomolgus monkeys, preladenant (1 or 3 mg/kg; PO) improved motor ability and did not evoke any dopaminergic-mediated dyskinetic or motor complications. In Cebus apella monkeys with a history of chronic haloperidol treatment, preladenant (0.3-3.0 mg/kg; PO) delayed the onset of EPS symptoms evoked by an acute haloperidol challenge. Collectively, these data support the use of preladenant for the treatment of PD and antipsychotic-induced movement disorders.

Potent and selective adenosine A2A receptor antagonists: 1,2,4-Triazolo[1,5-c]pyrimidines.

Antagonism of the adenosine A(2a) receptor offers great promise in the treatment of Parkinson's disease. In the course of exploring pyrazolo[4,3-e]-1,2,4-triazolo[1,5-c]pyrimidine A(2A) antagonists, which led to clinical candidate SCH 420814, we prepared 1,2,4-triazolo[1,5-c]pyrimidines with potent and selective (vs A(1)) A(2a) antagonist activity, including oral activity in the rat haloperidol-induced catalepsy model. Structure-activity relationships and plasma levels are described for this series.

Design, synthesis, and evaluation of fused heterocyclic analogs of SCH 58261 as adenosine A2A receptor antagonists.

SCH 58261 is a reported adenosine A(2A) receptor antagonist which is active in rat in vivo models of Parkinson's Disease upon ip administration. However, it has poor selectivity versus the A(1) receptor and does not demonstrate oral activity. Quinoline analogs have improved upon the selectivity and pharmacokinetics of SCH 58261, but were difficult to handle due to poor aqueous solubility. We report the design and synthesis of fused heterocyclic analogs of SCH 58261 with aqueous solubility as well as improved A(2A) receptor binding selectivity and pharmacokinetic properties. In particular, the tetrahydronaphthyridine 4s has excellent A(2A) receptor in vitro binding affinity and selectivity, is active orally in a rat in vivo model of Parkinson's Disease, and has aqueous solubility of 100 microM at physiological pH.

Biaryl and heteroaryl derivatives of SCH 58261 as potent and selective adenosine A2A receptor antagonists.

SCH 58261 is a reported adenosine A(2A) receptor antagonist, which is active in rat in vivo models of Parkinson's Disease upon ip administration. However, it has poor selectivity versus the A(1) receptor and does not demonstrate oral activity. We report the design and synthesis of biaryl and heteroaryl analogs of SCH 58261 which improve the A(2A) receptor binding selectivity as well as the pharmacokinetic properties of SCH 58261. In particular, the quinoline 25 has excellent A(2A) receptor in vitro binding affinity and selectivity, sustained rat plasma levels upon oral dosing, and is active orally in a rat behavioral assay.

Potent, selective, and orally active adenosine A2A receptor antagonists: arylpiperazine derivatives of pyrazolo[4,3-e]-1,2,4-triazolo[1,5-c]pyrimidines.

Antagonism of the adenosine A2A receptor offers great promise in the treatment of Parkinson's disease. Employing the known pyrazolo[4,3-e]-1,2,4-triazolo[1,5-c]pyrimidine A2A antagonist SCH 58261 as a starting point, we identified the potent and selective (vs. A1) antagonist 11h, orally active in the rat haloperidol-induced catalepsy model. We further optimized this lead to the methoxyethoxyethyl ether 12a (SCH 420814), which shows broad selectivity, good pharmacokinetic properties, and excellent in vivo activity.

Piperazine-based CCR5 antagonists as HIV-1 inhibitors. III: synthesis, antiviral and pharmacokinetic profiles of symmetrical heteroaryl carboxamides.

The unsymmetrical nicotinamide-N-oxide moiety in compound 1 was replaced with symmetrical isonicotinamides as well as 4,6-dimethyl pyrimidine-5-carboxamides. Compound 16 from the latter set reduced the number of rotamers, improved potency of inhibiting UIV entry, slightly diminished the affinity for the muscarine receptors and showed very good oral absorption.