Long-lasting angiotensin type 1 receptor binding and protection by candesartan: comparison with other biphenyl-tetrazole sartans

Vauquelin, Georges; Fierens, Frederik; Liefde, Isabelle Van

doi:10.1097/01.hjh.0000220403.61493.18

Cited by 42 publications

(20 citation statements)

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“…Such non-equilibrium single-point measurements do not capture the actual kinetics by which the small molecule binds to and, most importantly, subsequently resides on the human CRF 1 receptor in vivo (Fleck et al, 2012; Ramsey et al, 2011). Greater receptor antagonist efficacy is putatively associated with greater residence time on the receptor (Brinkerhoff et al, 2008; Fleck et al, 2012; Tummino and Copeland, 2008; Vauquelin et al, 2006; Vauquelin and Van Liefde, 2006), as exemplified in the greater efficacy and duration of action of candesartan, a slowly dissociating angiotensin II AT1 receptor antagonist (Lacourciere and Asmar, 1999; Verheijen et al, 2004), versus the more rapidly dissociating antagonist losartan (Hansson, 2001). Kinetic analysis of receptor association and dissociation rates at physiological temperatures demonstrated that R121919, with which positive preliminary clinical findings were obtained, exhibits a “kinetic” K i of ~0.36 nM, a potency underestimated by binding constants for it of 3–4 nM in standard competition assays (Fleck et al, 2012).…”

Section: Nonpeptide Crf1-selective Receptor Antagonistsmentioning

confidence: 99%

Behavioral, biological, and chemical perspectives on targeting CRF1 receptor antagonists to treat alcoholism

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Wit

et al. 2013

Drug and Alcohol Dependence

105

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Background Alcohol use disorders are chronic disabling conditions for which existing pharmacotherapies have only modest efficacy. In the present review, derived from the 2012 Behavior, Biology and Chemistry “Translational Research in Addiction” symposium, we summarize the anti-relapse potential of corticotropin-releasing factor type 1 (CRF1) receptor antagonists to reduce negative emotional symptoms of acute and protracted alcohol withdrawal and stress-induced relapse to alcohol seeking. Methods We review the biology of CRF1 systems, the activity of CRF1 receptor antagonists in animal models of anxiolytic and antidepressant activity, and experimental findings in alcohol addiction models. We also update the clinical trial status of CRF1 receptor antagonists, including pexacerfont (BMS-562086), emicerfont (GW876008), verucerfont (GSK561679), CP316311, SSR125543A, R121919/NBI30775, R317573/19567470/CRA5626, and ONO-2333Ms. Finally, we discuss the potential heterogeneity and pharmacogenomics of CRF1 receptor pharmacotherapy for alcohol dependence. Results The evidence suggests that brain penetrant-CRF1 receptor antagonists have therapeutic potential for alcohol dependence. Lead compounds with clinically desirable pharmacokinetic properties now exist, and longer receptor residence rates (i.e., slow dissociation) may predict greater CRF1 receptor antagonist efficacy. Functional variants in genes that encode CRF system molecules, including polymorphisms in Crhr1 (rs110402, rs1876831, rs242938) and Crhbp genes (rs10055255, rs3811939) may promote alcohol seeking and consumption by altering basal or stress-induced CRF system activation. Conclusions Ongoing clinical trials with pexacerfont and verucerfont in moderately to highly severe dependent anxious alcoholics may yield insight as to the role of CRF1 receptor antagonists in a personalized medicine approach to treat drug or alcohol dependence.

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Section: Nonpeptide Crf1-selective Receptor Antagonistsmentioning

confidence: 99%

Behavioral, biological, and chemical perspectives on targeting CRF1 receptor antagonists to treat alcoholism

Zorrilla

Heilig

Wit

et al. 2013

Drug and Alcohol Dependence

105

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“…Yet, there is increasing awareness that the time period over which they reside at their target also affects their clinical performance [1][2][3][4][5][6][7][8][9][10][11][12][13][14]. Examples of such slow-dissociating drugs have been enumerated and commented on in recent dedicated review articles [4,5,9,11].…”

Section: Introductionmentioning

confidence: 99%

Rebinding: or why drugs may act longerin vivothan expected from theirin vitrotarget residence time

Vauquelin

2010

Expert Opinion on Drug Discovery

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“…8 In vitro studies have shown that candesartan acts as an insurmountable antagonist and is able to virtually eliminate the AT 1 receptor-mediated effects of angiotensin II. 9 Compared with other widely used ARBs, candesartan shows high binding affinity for the AT 1 receptor, 9 that is, B80-fold higher than losartan and 10-fold higher than EXP 3174. Insurmountable antagonism provides long-lasting suppression of the reninangiotensin-aldosterone system, and it is suggested that this accounts for the magnitude of the antihypertensive efficacy of candesartan and for its sustained duration of effect.…”

Section: Introductionmentioning

confidence: 99%

Comparison of the efficacy of candesartan and losartan: a meta-analysis of trials in the treatment of hypertension

2009

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Informed by the findings from prospective observational studies and randomized outcome trials, guidelines for the management of hypertension acknowledge that the benefit of treatment can be attributed largely to blood pressure (BP) reduction. Therefore, quantification of differential BP lowering of different agents within classes of anti-hypertensives is of practical importance. The objective of this analysis was to compare the efficacy of candesartan and losartan with respect to reduction in systolic and diastolic BP (SBP and DBP). A systematic literature search of databases from 1980 to 1 October 2008 identified 13 studies in which candesartan and losartan were compared in randomized trials in hypertensive patients. Data from 4066 patients were included in the analysis using a random effect model. Mean changes in SBP and DBP were compared for each drug alone and after stratification for dose and for combination with hydrochlorothiazide (HCTZ). On the basis of all the data, the weighted mean difference favoured candesartan-3.22 mm Hg (95% confidence interval (CI) 2.16, 4.29) for SBP and 2.21 mm Hg (95% CI 1.34, 3.07) for DBP. These findings were consistent when analyses according to dose and combination with HCTZ were carried out. Thus, it can be concluded that at currently recommended doses, candesartan is more effective than losartan in lowering BP.

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Long-lasting angiotensin type 1 receptor binding and protection by candesartan: comparison with other biphenyl-tetrazole sartans

Abstract: Slow receptor dissociation and slow antagonist elimination are likely to act in synergy to produce long-lasting receptor protection.

Cited by 42 publications

References 50 publications

Behavioral, biological, and chemical perspectives on targeting CRF1 receptor antagonists to treat alcoholism

Behavioral, biological, and chemical perspectives on targeting CRF1 receptor antagonists to treat alcoholism

Rebinding: or why drugs may act longerin vivothan expected from theirin vitrotarget residence time

Comparison of the efficacy of candesartan and losartan: a meta-analysis of trials in the treatment of hypertension

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