Pharmacokinetics and disposition of a novel NMDA glycine site antagonist (UK-240,455) in rats, dogs and man

Webster, Robert O.; Cole, Susan; Gedge, Jenny I.; Roffey, S. J.; Walker, Don K.; Wild, W.

doi:10.1080/0049825031000085988

Cited by 7 publications

(9 citation statements)

References 15 publications

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“…As a result of the complexity of this phenomenon, various animal scaling approaches have been used in this study for the prediction of renal clearance in man for a diverse set of 34 marketed and 2 experimental drugs (Beaumont et al, 2000;Webster et al, 2003). The most basic animal scaling technique consists of using pharmacokinetics parameters obtained in preclinical species as a prediction for human (Boxenbaum, 1982).…”

Section: Introductionmentioning

confidence: 99%

Prediction of Human Renal Clearance from Preclinical Species for a Diverse Set of Drugs That Exhibit Both Active Secretion and Net Reabsorption

Paine

Ménochet²,

Denton³

et al. 2011

Drug Metab Dispos

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ABSTRACT:Identifying any extrahepatic excretion phenomenon in preclinical species is crucial for an accurate prediction of the pharmacokinetics in man. This understanding is particularly key for drugs with a small volume of distribution, because they require an especially low total clearance to be suitable for a once-a-day dosing regimen in man. In this study, three animal scaling techniques were applied for the prediction of the human renal clearance of 36 diverse drugs that show active secretion or net reabsorption: 1) direct correlations between renal clearance in man and each of the two main preclinical species (rat and dog); 2) simple allometry; and 3) Mahmood's renal clearance scaling method. The results show clearly that the predictions to man for the methods are improved significantly when corrections are made for species differences in plasma protein binding. Overall, the most accurate predictions were obtained by using a direct correlation with the dog renal clearance after correcting for differences in plasma protein binding and kidney blood flow (r 2 ‫؍‬ 0.84), where predictions, on average, were within 2-fold of the observed renal clearance values in human.

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Section: Introductionmentioning

confidence: 99%

Prediction of Human Renal Clearance from Preclinical Species for a Diverse Set of Drugs That Exhibit Both Active Secretion and Net Reabsorption

Paine

Ménochet²,

Denton³

et al. 2011

Drug Metab Dispos

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“…Such information will be helpful in identifying new classes of glycine antagonists such as subtype selective antagonists. Still challenges for the development of NMDA-glycine antagonists are present [85][86][87][88][89][90].…”

Section: Resultsmentioning

confidence: 99%

Tricyclic Quinoxalinediones, Aza-kynurenic Acids, and Indole-2- Carboxylic Acids as In Vivo Active NMDA-Glycine Antagonists

Nagata¹,

Katayama²,

Ohtani³

et al. 2006

CTMC

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This review article describes the development of in vivo active antagonists for the glycine binding site of the N-Methyl-D-Aspartate (NMDA) receptor. There were several difficulties in identifying a class of antagonists with in vivo efficacy and only a few compounds succeeded in emerging with activity in vivo. A series of tricyclic quinoxalinediones was highly potent glycine antagonists in vitro and the derivatives having a zwitterionic moiety including SM-18400 indeed showed in vivo activity. Similarly, tricyclic indole-2-carboxylic acids having a zwitterionic moiety such as SM-31900 were also active in vivo. In fact, SM-18400 and SM-31900 exhibited efficacy in several animal stroke models using intravenous infusion protocols. The practical syntheses of SM-18400 and SM-31900 as well as the novel synthesis of moderately active glycine antagonists, tricyclic azakynurenic acids, were also developed.

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“…Some of these compounds were found to be selective antagonists of AMPA receptors, such as 26 [33]; or dual antagonists acting both at glycine/NMDA and AMPA receptors, such as 27 [34] and 28 [35]; or selective antagonists of glycine/NMDA receptors, such as 29 [36]. A group of novel 5-(1-(heterocyclyl)-1-propyl) QXs, such as compound 30 [37], as well as UK-240,455 (31), a potent glycine/NMDA antagonists with good aqueous solubility and in vivo efficacy, also had been reported [38].…”

Section: Structure-activity Relationshipmentioning

confidence: 96%

Glycine/NMDA Receptor Antagonists as Potential CNS Therapeutic Agents: ACEA-1021 and Related Compounds

Cai¹

2006

CTMC

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Glutamate is the main excitatory neurotransmitter in central nervous system (CNS) and NMDA receptors are one of the major classes of ionotropic glutamate receptors. NMDA receptors have been known to play critical roles in normal CNS activities, as well as in many pathological conditions, including both acute and chronic diseases. The discovery of glycine as a coagonist of NMDA receptors has led to intensive research of glycine/NMDA antagonists as potential CNS drugs. The robust efficacy of glycine/NMDA antagonists, such as ACEA-1021 (5), in animal model of brain ischemia, together with good safety profile in animal models and in clinical trials, suggested that this class of NMDA antagonists should have good chance of success in the clinic as neuroprotectants. The clinical trial of ACEA-1021 for stroke was discontinued, mainly due to low solubility and lack of metabolism of the drug that led to the observation of crystals in the urine of some of the patients. However, through SAR studies, compounds such as ACEA-1416 (10) have been identified with improved properties, such as higher in vivo potency and site for potential metabolism. Therefore these compounds should be able to overcome some of the liabilities of ACEA-1021 and potentially could be developed as neuroprotectants. Based on the preclinical and clinical studies of glycine/NMDA antagonists, as well as the clinical experiences with t-PA, initiation of treatment within a short time window after the onset of stroke could be critical for the success of these antagonists in clinical trials. This can be accomplished by implementing the procedure developed for t-PA clinical trials, with modification based on the safety profile of glycine/NMDA antagonists, for future clinical trial to administer the drug as soon as possible after stroke onset. In addition, glycine/NMDA antagonists also have other potential therapeutic applications, such as for the treatment of traumatic brain injury, pain, cocaine overdose and convulsions.

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Pharmacokinetics and disposition of a novel NMDA glycine site antagonist (UK-240,455) in rats, dogs and man

Cited by 7 publications

References 15 publications

Prediction of Human Renal Clearance from Preclinical Species for a Diverse Set of Drugs That Exhibit Both Active Secretion and Net Reabsorption

Prediction of Human Renal Clearance from Preclinical Species for a Diverse Set of Drugs That Exhibit Both Active Secretion and Net Reabsorption

Tricyclic Quinoxalinediones, Aza-kynurenic Acids, and Indole-2- Carboxylic Acids as In Vivo Active NMDA-Glycine Antagonists

Glycine/NMDA Receptor Antagonists as Potential CNS Therapeutic Agents: ACEA-1021 and Related Compounds

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