Design, Synthesis and Biological Evaluation of a Novel Series of Potent, Orally Active Adenosine A&lt;SUB&gt;1&lt;/SUB&gt; Receptor Antagonists with High Blood-Brain Barrier Permeability

Kuroda, Satoru; Takamura, Fujiko; Tenda, Yoshiyuki; Itani, Hiromichi; Tomishima, Yasuyo; Akahane, Atsushi; Sakane, Kazuo

doi:10.1248/cpb.49.988

Cited by 27 publications

(5 citation statements)

References 19 publications

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“…Stemming from their search for CNS-penetrant adenosine A 1 receptor antagonists, Kuroda and co-workers described another example of replacing carboxylic acid functionality to increase BBB permeability . This subtype of the adenosine family of receptors is expressed at high levels in the cortex and hippocampus, and antagonists have been proposed as potential therapeutics for cognitive disorders.…”

Section: Optimizing Passive Diffusionmentioning

confidence: 99%

Structure−Brain Exposure Relationships

2006

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Section: Optimizing Passive Diffusionmentioning

confidence: 99%

Structure−Brain Exposure Relationships

2006

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“…Each row of Table corresponds to a particular biological assay, designated in its upper left-hand corner by a name and its catalog reference number in square brackets. The query structure associated with that assay is shown at the left, accompanied by a literature reference in square brackets and its reported potency (micromolar) in parentheses. − Next to the query structure is an example of a hit structure, one first identified by a topomer similarity search using the query structure shown and then found experimentally to have the same activity as the query, with its micromolar potency established by IC 50 determination shown in parentheses. The structures of both query and example hit have been drawn to emphasize their apparent shape similarity.…”

Section: Resultsmentioning

confidence: 99%

“Lead Hopping”. Validation of Topomer Similarity as a Superior Predictor of Similar Biological Activities

Cramer¹,

Jilek²,

Guessregen³

et al. 2004

J. Med. Chem.

119

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Two extensive studies quantifying the ability of topomer shape similarity to forecast a variety of biological similarities are described. In a prospective trial of "lead hopping", using topomer similarity for virtual screening and queries from the patent literature, biological assays of 308 selected compounds (representing 0.03% of those available, per assay type) yielded 11 successful "lead hops" in the 13 assays attempted. The hit rate averaged over all assays was 39% ("activity"defined as inhibition > or =20% at 10 microM), significantly greater than an unexpectedly high negative control hit rate of 15%. The average "Tanimoto 2D fingerprint similarity" between query and "lead hop" structures (0.36) was little more than the Tanimoto similarity between random drug-like structures. Topomer shape and Tanimoto 2D fingerprint similarities were also compared retrospectively, in their tendencies to concentrate together potential and actual drugs reported to belong to the same "activity class", for twenty classes. Among the most similar 3% of structures (corresponding to "> or =0.85 Tanimoto" for these structures), an average of 62% of the topomer similar selection possessed a near neighbor belonging to the same activity class, roughly a one-third superiority over the "Tanimoto > or = 0.85" selection containing 48% actives in avoiding false positives. Conversely, the least similar 75% of structures contained 0.3% actives for topomer similarity vs 1.0% actives for Tanimoto 2D fingerprint similarity, a 3-fold superiority for topomers in avoiding false negatives.

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“…1, Table 1) and two of them have been used in clinical studies up to now. Recently, a nonxanthine-type PET ligand has been prepared from pyrazolopyridine analogs [50].…”

Section: Adenosine a 1 Receptor Ligandsmentioning

confidence: 99%

PET Tracers for Mapping Adenosine Receptors as Probes for Diagnosis of CNS Disorders

Ishiwata¹,

Kimura²,

Vries³

et al. 2007

CNSAMC

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Adenosine is an endogenous modulator of several physiological functions in the central nervous system (CNS). The effect is mediated by a receptor family that consists of at least four subtypes: A 1 , A 2A , A 2B and A 3 receptors. The adenosine receptors play a role in neurological and psychiatric disorders such as Alzheimer's disease, Parkinson's disease, epilepsy and schizophrenia. Knowledge on adenosine receptor densities and status are important for understanding the mechanisms underlying the pathogenesis of diseases and for developing new therapeutics. Positron emission tomography (PET) offers a non-invasive tool to investigate these features in vivo, provided that suitable radiopharmaceuticals are available. As a consequence of the development of xanthine-type adenosine receptor antagonists with high affinity and high selectivity, several PET ligands labeled with carbon-11 (half-life of 20.4 min) and fluorine-18 (half-life of 109.8 min) have been proposed for mapping the adenosine A 1 and A 2A receptors (A 1 R and A 2A R, respectively) and the adenosine uptake site in the CNS since 1995. Later non-xanthine-type antagonists for A 2A R were radiolabeled. So far two tracers for A 1 R, [ 18 F]CPFPX and [ 11 C]MPDX, and a tracer for A 2A R, [ 11 C]TMSX (also called [ 11 C]KF18446), have been applied to humans. For the other subtypes and the adenosine uptake site no suitable radioligands have been developed yet. This paper gives an overview of the current status on PET tracers for mapping adenosine receptors and the development of new compounds that may lead to new PET tracers.

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Design, Synthesis and Biological Evaluation of a Novel Series of Potent, Orally Active Adenosine A<SUB>1</SUB> Receptor Antagonists with High Blood-Brain Barrier Permeability

Cited by 27 publications

References 19 publications

Structure−Brain Exposure Relationships

Structure−Brain Exposure Relationships

“Lead Hopping”. Validation of Topomer Similarity as a Superior Predictor of Similar Biological Activities

PET Tracers for Mapping Adenosine Receptors as Probes for Diagnosis of CNS Disorders

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