Synthesis and SAR of highly potent and selective dopamine D3-receptor antagonists: Variations on the 1H-pyrimidin-2-one theme

Geneste, Hervé; Amberg, Wilhelm; Backfisch, Gisela; Beyerbach, Armin; Braje, Wilfried M.; Delzer, Jürgen; Haupt, Andreas; Hutchins, Charles W.; King, Linda L.; Sauer, Daryl R.; Unger, Liliane; Wernet, Wolfgang

doi:10.1016/j.bmcl.2005.12.079

Cited by 25 publications

(20 citation statements)

References 8 publications

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“…1 We recently reported that ABT-925 regimens of 50 and 150 mg QD were well tolerated, but did not significantly improve schizophrenia symptoms in acutely ill patients. 2 A positron emission tomography study revealed that these regimens resulted in <60% receptor occupancy of ABT-925 at the D3 receptor, 3 suggesting that the hypothesis of D3 receptor antagonism for the treatment of schizophrenia may not have been fully tested.…”

Section: Introductionmentioning

confidence: 95%

Association of dopamine-related genetic loci to dopamine D3 receptor antagonist ABT-925 clinical response

et al. 2013

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ABT-925, a selective dopamine D3 receptor (DRD3) antagonist, was tested in schizophrenia. A DRD3 gene polymorphism results in an S9G amino-acid change that has been associated with lower risk of schizophrenia, higher affinity for dopamine and some antipsychotics, and differential response to some antipsychotics. The effect of S9G genotype on response to ABT-925 was examined. DNA samples (N=117) were collected in a proof-of-concept, double-blind, randomized, placebo-controlled study of ABT-925 (50 or 150 mg QD) in acute exacerbation of schizophrenia. A pre-specified analysis assessed impact of genotype (SS versus SG+GG) on change from baseline to final evaluation for the Positive and Negative Syndrome Scale (PANSS) total score using analysis of covariance with genotype, treatment and genotype-by-treatment interaction as factors, and baseline score as covariate. Significant genotype-by-treatment interaction (P=0.015) was observed for change from baseline to final evaluation for the PANSS total score. Within subgroup analyses showed significant improvement from placebo in the SG+GG group treated with ABT-925 150 mg. More favorable clinical outcomes were observed in patients treated with ABT-925 150 mg who carried the DRD3 G allele than in those who carried the DRD3 SS genotype.

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Section: Introductionmentioning

confidence: 95%

Association of dopamine-related genetic loci to dopamine D3 receptor antagonist ABT-925 clinical response

et al. 2013

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“…In order to overcome this trouble, Ertl et al [4] developed a very fast additive fragment method of calculating PSA especially for rapid virtual bioavailability screening of a very large collection of molecules. Since the first report of this topological polar surface area (TPSA), it has become extremely popular in medicinal chemistry for virtual screening [5][6][7][8] and for predicting ADME properties, including blood-brain barrier crossing tendency [9][10][11][12][13][14][15][16][17][18]. Recently, Ertl reviewed the use of polar surface area in medicinal chemistry research [19].…”

Section: Introductionmentioning

confidence: 99%

Topological Polar Surface Area: A Useful Descriptor in 2D-QSAR

Sivaprakasam¹,

Doerksen²

2009

CMC

298

147

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Topological polar surface area (TPSA), which makes use of functional group contributions based on a large database of structures, is a convenient measure of the polar surface area that avoids the need to calculate ligand 3D structure or to decide which is the relevant biological conformation or conformations. We demonstrate the utility of TPSA in 2D-QSAR for 14 sets of diverse pharmacological activity data. Even though a large pool of reports showing the importance of the classic 2D descriptors such as calculated logP (ClogP) and calculated molar refractivity (CMR) exists in the 2D-QSAR literature, this is the first report to demonstrate the value of TPSA as a relevant descriptor applicable to a large, structurally and pharmacologically diverse set of classes of compounds. We also address the limitations of applicability of this descriptor for 2D-QSAR analysis. We observed a negative correlation of TPSA with activity data for anticancer alkaloids, MT1 and MT2 agonists, MAO-B and tumor necrosis factor-alpha inhibitors and a positive correlation with inhibitory activity data for telomerase, PDE-5, GSK-3, DNA-PK, aromatase, malaria, trypanosomatids and CB2 agonists.

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“…ABT-925, also known as A-437203 or BSF-201640, is a D 3 receptor antagonist with 45-to 120-fold higher in-vitro affinity for the D 3 than the D 2 receptor (Chaperon et al 2003 ;Geneste et al 2006 ;Gross et al 1997Gross et al , 2006. ABT-925, also known as A-437203 or BSF-201640, is a D 3 receptor antagonist with 45-to 120-fold higher in-vitro affinity for the D 3 than the D 2 receptor (Chaperon et al 2003 ;Geneste et al 2006 ;Gross et al 1997Gross et al , 2006.…”

Section: Introductionmentioning

confidence: 99%

Blockade of [11C](+)-PHNO binding in human subjects by the dopamine D3 receptor antagonist ABT-925

Graff‐Guerrero

Redden

Abi-Saab

et al. 2009

Int. J. Neuropsychopharm.

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Dopamine D3 receptors are preferentially localized in the limbic system and midbrain, and thus may be involved in the pathophysiology of neuropsychiatry disorders. [11C](+)-PHNO is the first preferential D3 receptor radioligand in humans, yet there are no blockade studies with a D3 receptor antagonist in humans. This study characterized the blockade of [11C](+)-PHNO binding by ABT-925, a D3 receptor antagonist, in healthy male subjects. Sixteen subjects underwent 2-3 positron emission tomography (PET) scans, at baseline and following one or two doses of ABT-925 ranging from 50 mg to 600 mg. Receptor occupancies were estimated for globus pallidus, substantia nigra, caudate, putamen, and ventral striatum. At the 600-mg dose (n=9), ABT-925 receptor occupancy (mean+/-s.d.) was higher in substantia nigra (75+/-10%) and globus pallidus (64+/-22%) than in ventral striatum (44+/-17%), caudate (40+/-18%) and putamen (38+/-17%) (ANOVA: F4,140=15.02, p<0.001). The fractions of [11C](+)-PHNO binding attributable to D3 receptors in D3 receptor-rich regions were 100% (substantia nigra) and 90% (globus pallidus), and in D2 receptor-rich regions were 55% (caudate) and 53% (putamen). The ED50 of ABT-925 was 4.37 microg/ml across regions. Our results demonstrate that [11C](+)-PHNO binding can be blocked by a D3 receptor antagonist and confirm preclinical findings that [11C](+)-PHNO signal in the substantia nigra and globus pallidus is mainly reflective of its binding to D3 receptors. Thus, [11C](+)-PHNO seems a suitable PET radiotracer to estimate D3 receptor occupancy in humans.

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Synthesis and SAR of highly potent and selective dopamine D3-receptor antagonists: Variations on the 1H-pyrimidin-2-one theme

Cited by 25 publications

References 8 publications

Association of dopamine-related genetic loci to dopamine D3 receptor antagonist ABT-925 clinical response

Association of dopamine-related genetic loci to dopamine D3 receptor antagonist ABT-925 clinical response

Topological Polar Surface Area: A Useful Descriptor in 2D-QSAR

Blockade of [11C](+)-PHNO binding in human subjects by the dopamine D3 receptor antagonist ABT-925

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