Synthetic studies on selective adenosine A2A receptor antagonists: Synthesis and structure–activity relationships of novel benzofuran derivatives

Saku, Osamu; Saki, Mayumi; Kurokawa, Masako; Ikeda, Ken; Takizawa, Takuya; Uesaka, Noriaki

doi:10.1016/j.bmcl.2009.12.028

Cited by 38 publications

(17 citation statements)

References 9 publications

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“…A high‐throughput screening performed by the Kyowa Hakko group resulted in the identification of the benzofuran hit 72 (Fig. ), displaying micromolar affinity for the A 2A AR (58% and 86% binding inhibition at 10 −7 and 10 −6 mol/L, respectively) and about 50% inhibition of CGS21680‐mediated catalepsy in vivo at 10 mg/kg, p.o . The introduction of a 4‐phenyl group to replace the methoxycarbonyl functionality, such as in compound 73, enhanced binding affinity (83% and 100% binding inhibition at 10 and 100 nM, respectively), as well as in vivo potency (74% catalepsy inhibition at 10 mg/kg, p.o.).…”

Section: Medicinal Chemistry Of A2a Antagonistsmentioning

confidence: 99%

“…Istradefylline (KW6002, 38, Fig. 7) is the only compound of this class that entered clinical trials and the 157 59 (r) 46 157 114 (r) 47, 161 190 1010 c 36 c 69 193 222 c 11 c 199 100 (58%) e 73 199 100 (100%) e 74 199 1000 100 1000 (4%) f (73%) e (21%) f 75 201 0.5 76 202 1 77 203 0.50 78 203 0.50 79, 28 only A 2A antagonist that has been licensed for use as an antiparkinsonian drug in Japan (see Section 6 for details). 101 The advancement of 8-styrylxanthines as drugs undoubtedly has been hampered by physicochemical liabilities, such as poor water solubility and light sensitivity.…”

Section: Xanthine-based Derivativesmentioning

confidence: 99%

“…11), displaying micromolar affinity for the A 2A AR (58% and 86% binding inhibition at 10 −7 and 10 −6 mol/L, respectively) and about 50% inhibition of CGS21680-mediated catalepsy in vivo at 10 mg/kg, p.o. 199 The introduction of a 4-phenyl group to replace the methoxycarbonyl functionality, such as in compound 73, enhanced binding affinity (83% and 100% binding inhibition at 10 and 100 nM, respectively), as well as in vivo potency (74% catalepsy inhibition at 10 mg/kg, p.o.). Inversion of the amide moiety at C 2 with arylcarbamate or arylurea functions led to a general decrease of in vitro potency.…”

Section: H Benzofuransmentioning

confidence: 99%

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History and Perspectives of A_2AAdenosine Receptor Antagonists as Potential Therapeutic Agents

Preti

Baraldi

Moorman³

et al. 2015

Med. Res. Rev.

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Growing evidence emphasizes that the purine nucleoside adenosine plays an active role as a local regulator in different pathologies. Adenosine is a ubiquitous nucleoside involved in various physiological and pathological functions by stimulating A1 , A2A , A2B , and A3 adenosine receptors (ARs). At the present time, the role of A2A ARs is well known in physiological conditions and in a variety of pathologies, including inflammatory tissue damage and neurodegenerative disorders. In particular, the use of selective A2A antagonists has been reported to be potentially useful in the treatment of Parkinson's disease (PD). In this review, A2A AR signal transduction pathways, together with an analysis of the structure-activity relationships of A2A antagonists, and their corresponding pharmacological roles and therapeutic potential have been presented. The initial results from an emerging polypharmacological approach are also analyzed. This approach is based on the optimization of the affinity and/or functional activity of the examined compounds toward multiple targets, such as A1 /A2A ARs and monoamine oxidase-B (MAO-B), both closely implicated in the pathogenesis of PD.

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Section: Medicinal Chemistry Of A2a Antagonistsmentioning

confidence: 99%

Section: Xanthine-based Derivativesmentioning

confidence: 99%

Section: H Benzofuransmentioning

confidence: 99%

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History and Perspectives of A_2AAdenosine Receptor Antagonists as Potential Therapeutic Agents

Preti

Baraldi

Moorman³

et al. 2015

Med. Res. Rev.

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“…Further optimization of this scaffold led to the urea compound 55 which had good potency for A 2A and was 270-fold and >4000-fold selective versus A series of 4-aryl substituted benzofurans was identified, and the 4-phenyl-substituent was found to be the most consistent group for A 2A activity (Figure 17). 62 The morpholine amide 56 showed good affinity for A 2A and significantly reversed (78%) CGS-induced catalepsy in mice at 10 mg/kg, p.o. Further exploration of this scaffold showed that the methyl carbamate 57 also had good A 2A activity and reversed catalepsy by 86% at 10 mg/kg, p.o.…”

Section: Acs Chemical Neurosciencementioning

confidence: 95%

Adenosine A_2A Receptor Antagonists and Parkinson’s Disease

Shook

Jackson

2011

ACS Chem. Neurosci.

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P arkinson's disease (PD) is a chronic, progressive neurologicaldisease that affects ∼1% of the population over the age of 65. 1 It is characterized by progressive impairment in motor function that is often accompanied by disturbances in mood and cognitive function. The majority of motor impairments of PD are caused by a gradual loss of dopamine (DA) producing neurons in the ventral midbrain and concomitant loss of DA input to forebrain (striatal) motor structures. 2,3 The loss of DA input to the neostriatum leads to dysregulation of striatal function and the classic motor symptoms of PD, such as resting tremor, muscular rigidity, and bradykinesia.The majority of treatments aim to restore dopamine signaling and thereby reduce the severity of the motor symptoms. Dopamine replacement therapy using L-DOPA, the precursor to dopamine, remains the gold-standard treatment for PD. Other approaches include inhibition of DA turnover using monoamine oxidase type B (MAO-B) inhibitors, 4 catechol O-methyl-transferase (COMT) inhibitors, 5 and inhibition of dopamine reuptake 6 or direct agonists 7 of postsynaptic dopamine receptors. Although the dopamine targeted therapies work well to address the PD related motor disturbances, they all produce undesirable side effects (dyskinesia, hallucinations, onÀoff effects) that become more severe and problematic with continued treatment. Also, the aforementioned therapies typically show reduced efficacy as motor functions deteriorate and the disease progresses. Moreover, these treatments do not alter disease progression and do not address the mood, postural instability, or cognitive disturbances that frequently accompany PD.The dopamine replacement agents have significant limitations which influenced researchers to find nondopamine based treatments for PD. One nondopaminergic approach that has received considerable attention is modulation of adenosine receptors which is the topic highlighted in this Review. 8 Adenosine is a neuromodulator that coordinates responses to dopamine and other neurotransmitters in areas of the brain that are responsible for motor function, mood, and learning and memory. 9 Adenosine comprises four distinct receptor subtypes designated A 1 , A 2A , A 2B , and A 3 belonging to the G protein-coupled receptor superfamily. 10 Adenosine A 1 and A 3 receptors are coupled to inhibitory G proteins, while A 2A and A 2B receptors are coupled to stimulatory G proteins. Autoradiography studies in rodents showed that the greatest densities of A 2A receptors are found in the striatum 11 which closely matches the distribution in humans based on PET imaging. 12 As described above, loss of dopamine input into the neostriatum is a hallmark of PD and causes many of the cardinal motor symptoms of this disorder. In the striatum adenosine A 2A receptors colocalize and physically associate with dopamine D 2 receptors. ABSTRACT: This Review summarizes and updates the work on adenosine A 2A receptor antagonists for Parkinson's disease from 2006 to the present. There have been numerou...

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“…A wide range of natural compounds contain such moieties,2 and numerous biologically active benzofurans are known to exert anti‐inflammatory, anti‐arrhythmic, haemostatic, anti‐bacterial, fungicidal, anti‐viral, anti‐tumor, and anti‐oxidant activities 3. Some of them are promising drugs against Parkinson's3e and Alzheimer's disease 3f…”

Section: Introductionmentioning

confidence: 99%

A New Synthesis of 3‐(Sulfonamido)benzofurans through an Acid‐Promoted Cascade Reaction of N‐(2,2‐Dichloro‐2‐phenylethylidene)arenesulfonamides with para‐Substituted Phenols

et al. 2011

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Synthetic studies on selective adenosine A2A receptor antagonists: Synthesis and structure–activity relationships of novel benzofuran derivatives

Cited by 38 publications

References 9 publications

History and Perspectives of A_2AAdenosine Receptor Antagonists as Potential Therapeutic Agents

History and Perspectives of A_2AAdenosine Receptor Antagonists as Potential Therapeutic Agents

Adenosine A_2A Receptor Antagonists and Parkinson’s Disease

A New Synthesis of 3‐(Sulfonamido)benzofurans through an Acid‐Promoted Cascade Reaction of N‐(2,2‐Dichloro‐2‐phenylethylidene)arenesulfonamides with para‐Substituted Phenols

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Synthetic studies on selective adenosine A2A receptor antagonists: Synthesis and structure–activity relationships of novel benzofuran derivatives

Cited by 38 publications

References 9 publications

History and Perspectives of A2AAdenosine Receptor Antagonists as Potential Therapeutic Agents

History and Perspectives of A2AAdenosine Receptor Antagonists as Potential Therapeutic Agents

Adenosine A2A Receptor Antagonists and Parkinson’s Disease

A New Synthesis of 3‐(Sulfonamido)benzofurans through an Acid‐Promoted Cascade Reaction of N‐(2,2‐Dichloro‐2‐phenylethylidene)arenesulfonamides with para‐Substituted Phenols

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History and Perspectives of A_2AAdenosine Receptor Antagonists as Potential Therapeutic Agents

History and Perspectives of A_2AAdenosine Receptor Antagonists as Potential Therapeutic Agents

Adenosine A_2A Receptor Antagonists and Parkinson’s Disease