This article describes RegioSelectivity-Predictor (RS-Predictor), a new in silico method for generating predictive models of P450-mediated metabolism for drug-like compounds. Within this method, potential sites of metabolism (SOMs) are represented as "metabolophores": A concept that describes the hierarchical combination of topological and quantum chemical descriptors needed to represent the reactivity of potential metabolic reaction sites. RS-Predictor modeling involves the use of metabolophore descriptors together with multiple-instance ranking (MIRank) to generate an optimized descriptor weight vector that encodes regioselectivity trends across all cases in a training set. The resulting pathway-independent (O-dealkylation vs N-oxidation vs Csp(3) hydroxylation, etc.), isozyme-specific regioselectivity model may be used to predict potential metabolic liabilities. In the present work, cross-validated RS-Predictor models were generated for a set of 394 substrates of CYP 3A4 as a proof-of-principle for the method. Rank aggregation was then employed to merge independently generated predictions for each substrate into a single consensus prediction. The resulting consensus RS-Predictor models were shown to reliably identify at least one observed site of metabolism in the top two rank-positions on 78% of the substrates. Comparisons between RS-Predictor and previously described regioselectivity prediction methods reveal new insights into how in silico metabolite prediction methods should be compared.

01 Aug 2010·European Journal of PharmacologyQ3 · MEDICINE

α1-Adrenoceptor activation is involved in the central N-methyl-d-aspartate-induced adrenomedullary outflow in rats

Q3 · MEDICINE

Article

Author: Okada, Shoshiro ; Yamaguchi, Naoko

N-methyl-D-aspartate (NMDA) has been implicated in the regulation of several autonomic responses in the brain. The present study determined whether activation of alpha1-adrenoceptors is involved in the centrally administered NMDA-induced adrenomedullary catecholamine outflow, using urethane-anesthetized rats. The NMDA (5.0 nmol/animal, i.c.v.)-induced elevation of plasma levels of noradrenaline and adrenaline was reduced by phentolamine (0.33 micromol/animal, i.c.v.), a non-selective alpha-adrenoceptor antagonist, and by 2-{[b-(4-hydroxyphenyl)ethyl]aminomethyl}-1 tetralone (HEAT) (90.0 nmol/animal, i.c.v.), a selective alpha1-adrenoceptor antagonist. In contrast, sotalol (0.8 micromol/animal, i.c.v.), a non-selective beta-adrenoceptor antagonist, did not alter the responses. In addition, U-73122, a phospholipase C inhibitor (5.0 nmol/animal, i.c.v.), RHC-80267, a diacylglycerol lipase inhibitor (1.3 micromol/animal, i.c.v.) and URB 602, a monoacylglycerol lipase inhibitor (0.85 and 1.7 micromol/animal, i.c.v.), reduced the NMDA-induced plasma elevation of both catecholamines. Furthermore, perfusion of the hypothalamic paraventricular nucleus with NMDA (0.3 and 1.0 mM) dose-dependently elevated both noradrenaline levels in the hypothalamic paraventricular nucleus and plasma catecholamine levels. These responses were abolished by co-administration of dizocilpine malate (MK-801, 0.1 mM), a selective non-competitive antagonist of the NMDA receptor and by co-administration of (+)-S-145 (2.5 mM), a selective competitive antagonist of the thromboxane A2 receptor. These results suggest that activation of central alpha1-adrenoceptors is involved in the centrally administered NMDA-induced activation of adrenomedullary catecholamine outflow in rats. Furthermore, signaling cascades downstream of the alpha1-adrenoceptor in the hypothalamic paraventricular nucleus may play an important role in the process.

01 Mar 2009·European Journal of PharmacologyQ3 · MEDICINE

Brain cyclooxygenase and prostanoid TP receptors are involved in centrally administered epibatidine-induced secretion of noradrenaline and adrenaline from the adrenal medulla in rats

Q3 · MEDICINE

Article

Author: Yokotani, Kunihiko ; Shimizu, Takahiro

Plasma adrenaline mainly originates from adrenaline-containing cells in the adrenal medulla, whereas plasma noradrenaline reflects not only the release from sympathetic nerves but also the secretion from noradrenaline-containing cells in the adrenal medulla. The present study was undertaken to examine the mechanisms involved in centrally administered epibatidine (a potent agonist of nicotinic acethylcholine receptors)-induced elevation of plasma catecholamines with regard to the brain prostanoid. Intracerebroventricularly (i.c.v.) administered epibatidine (1, 5 and 10 nmol/animal) effectively elevated plasma noradrenaline and adrenaline. The epibatidine (5 nmol/animal, i.c.v.)-induced elevation of both catecholamines was attenuated by hexamethonium (an antagonist of nicotinic acethylcholine receptors) (0.9 and 1.8 micromol/animal, i.c.v.), indomethacin (an inhibitor of cyclooxygenase) (0.6 and 1.2 micromol/animal, i.c.v.) and (+)-S-145 (an antagonist of prostanoid TP receptors) (0.6 and 1.3 micromol/animal, i.c.v.), and abolished by acute bilateral adrenalectomy. On the other hand, intravenously administered epibatidine (5 nmol/animal) was largely ineffective on the plasma levels of catecholamines, and intravenous pretreatment with hexamethonium (1.8 micromol/animal) had no effect on the epibatidine (5 nmol/animal, i.c.v.)-induced elevation of both catecholamines. These results suggest that centrally administered epibatidine activates the brain nicotinic acethylcholine receptors, thereby evoking the secretion of noradrenaline and adrenaline from the adrenal medulla by brain cyclooxygenase- and prostanoid TP receptor-mediated mechanisms in rats.

100 Deals associated with S-145

R&D Status

10 top R&D records.

to view more data

Indication	Highest Phase	Country/Location	Organization	Date
Asthma	Phase 2	Japan	Shionogi & Co., Ltd.	-
Myocardial Infarction	Phase 2	Japan	Shionogi & Co., Ltd.	-

Clinical Result

Indication

Phase

Evaluation

View All Results

Translational Medicine

Boost your research with our translational medicine data.

view full example data

Deal

Boost your decision using our deal data.

view full example data

Core Patent

Boost your research with our Core Patent data.

view full example data

Clinical Trial

Identify the latest clinical trials across global registries.

view full example data

Approval

Accelerate your research with the latest regulatory approval information.

view full example data

Regulation

Understand key drug designations in just a few clicks with Synapse.

view full example data

Chat with Hiro

Get started for free today!

Accelerate Strategic R&D decision making with Synapse, PatSnap’s AI-powered Connected Innovation Intelligence Platform Built for Life Sciences Professionals.

Start your data trial now!

Synapse data is also accessible to external entities via APIs or data packages. Empower better decisions with the latest in pharmaceutical intelligence.

Bio

Bio Sequences Search & Analysis

Chemical

Chemical Structures Search & Analysis


No Data

S-145

Overview

Basic Info

Structure/Sequence

Related

R&D Status

Clinical Result

Translational Medicine

Deal

Core Patent

Clinical Trial

Approval

Regulation