Design and Characterization of Optimized Adenosine A_2A/A₁ Receptor Antagonists for the Treatment of Parkinson's Disease

Abstract

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.

History and Perspectives of A2AAdenosine Receptor Antagonists as Potential Therapeutic Agents

“…A library of indeno[1,2‐ d ]pyrimidin‐5‐one derivatives (see compounds 30–33 , Fig. , Table ) has been screened by the Janssen group (Pennsylvania, USA) that detected a promising binding profile for the new tricyclic chemotype . Hit‐optimization furnished very potent A 1 /A 2A dual antagonists with remarkable in vivo potency .…”

“…In particular, A 1 antagonists stimulate dopamine release at the presynaptic level, while A 2A antagonists enhance postsynaptic responsiveness to dopamine, revealing a rationale for the development of dual antagonists in PD treatment. In addition, A 1 AR blockade is known to have positive effects on PD‐related cognitive disorders …”

“…Morpholine 32 showed improved in vivo potency (ED 50 < 0.1 mg/kg in the mouse catalepsy model, p.o. ), excellent brain exposure, was devoid of the metabolic liability seen with 31 , and exhibited a promising pharmacokinetic profile in mouse, rat, and monkey . Preclinical studies performed in rat with JNJ40255293 have shown beneficial effects on cognitive functions due to the interaction with A 1 ARs, while the increase of motor activity is mediated by A 2A AR blockade.…”

Bioactivation of the Cannabinoid Receptor Antagonist Rimonabant to a Cytotoxic Iminium Ion Metabolite

“…Case examples linking α-carbon oxidation of cyclic tertiary amines and iminium ions to covalent binding have been reported in the literature, 7−10 which include a report of genotoxicity caused by covalent modification of DNA. 11,12 These results raise the possibility that metabolic bioactivation of rimonabant could have toxicological consequences, especially in view of the key role played by reactive metabolites in the toxicity of many other drugs and foreign compounds. 13 In support of this possibility, recently it has been found that rimonabant exhibits potentiated in vitro toxicity to human liver derived THLE cell lines, which expressed P450 3A4 compared to THLE cells that expressed no P450 activity.…”

Stabilised G protein-coupled receptors in structure-based drug design: a case study with adenosine A2A receptor

“…ZM241385) or guanine (e.g. vipadenant 97 ); some antagonists which are not derived from purines have recently shown efficacy in preclinical models of PD, such as Lu AA47070,98,99 SYN-115 100 and 2-amino-8-(4-methylpiperazine-1-carbonyl)-4-phenyl-5H-indeno[1,2-d]pyrimidin-5-one 101. Preladenant is phase III clinical trials for the treatment of PD 45.…”