Delving into the Latest Updates on ZD-6416 with Synapse

Overview

Basic Info

Drug Type

Small molecule drug

Synonyms

ZD 6416

Target

EP1

Mechanism

EP1 antagonists(Prostanoid EP1 receptor antagonists)

Therapeutic Areas

Nervous System Diseases

Active Indication-

Inactive Indication

NeuralgiaPain

Originator Organization

AstraZeneca Pharmaceuticals Co. Ltd.

Active Organization-

Inactive Organization

AstraZeneca Pharmaceuticals Co. Ltd.

AstraZeneca PLC

Drug Highest PhaseDiscontinuedPhase 2

First Approval Date-

Regulation-

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Prostaglandins are central to the processes of human labor. Prostaglandin E(2) (PGE(2)) synthesized within the uterus mediates cervical ripening and uterine contractions. PGE receptors, EP1 and EP3, may each mediate contractions, and represent potential therapeutic targets in the management of preterm labor. Studies of the expression and function of EP1 and EP3 in pregnant myometrium are inconsistent.

OBJECTIVE:

The objective of the study was to determine the relative importance of EP1 and EP3 in human myometrial contractility.

DESIGN:

We studied the expression of EP1 and EP3 in upper- and lower-segment myometrium at term in vivo and the effects of specific inhibitors on contractions in vitro.

PATIENTS:

Myometrial biopsies for both in vivo and in vitro studies were taken at cesarean section at term before or in labor in uncomplicated pregnancies.

RESULTS:

We found no differences in the expression of EP1 or EP3 at mRNA or protein level between the upper and lower segment myometrium and no overall changes associated with the onset of labor. Upon labor, EP1, but not EP3, was found to relocalize to the nucleus. In studies of contractility, we found no differences in spontaneous or PGE(2)-induced contractility between the upper- and lower-segment samples. Spontaneous contractions were inhibited by acetylsalicylic acid and were rescued by PGE(2). Although an EP1 antagonist, ZD6416, had no effect, an EP3 antagonist, L798106, inhibited both spontaneous and PGE(2)-induced contractions.

CONCLUSIONS:

EP3 is the primary receptor subtype that mediates PGE(2) induced contractility in human pregnant myometrium at term and represents a possible therapeutic target.

01 Jan 2003·GastroenterologyQ1 · MEDICINE

The prostaglandin E2 receptor-1 (EP-1) mediates acid-induced visceral pain hypersensitivity in humans

Q1 · MEDICINE

Article

Author: Clifford J. Woolf ; Jim Growcott ; Sanchoy Sarkar ; Anthony R. Hobson ; David G. Thompson ; Qasim Aziz ; Andrew Hughes

BACKGROUND & AIMS:

Central sensitization, an activity-dependent increase in spinal cord neuronal excitability, has been shown to contribute to esophageal pain hypersensitivity. Prostaglandin E2 (PGE(2)) is a mediator in both peripheral and central sensitization, in part via the prostaglandin E2 receptor-1 (EP-1), and may be a potential target for treating visceral pain. The purpose of this study was to determine whether acid-induced pain hypersensitivity within the non-acid-exposed esophagus (secondary hyperalgesia) is mediated by PGE(2) activation of the EP-1 receptor.

METHODS:

Twelve healthy male subjects participated in a randomized, placebo-controlled crossover study. Upper esophageal pain thresholds (PTs) to electrical stimulation were determined, and either the EP-1 antagonist ZD6416 or a placebo was orally administered. One-hour after dosing, acid or saline (0.15 mol/L) was infused into the lower esophagus for 30 minutes. Upper esophageal PT was monitored for 120 minutes after infusion.

RESULTS:

Except in 1 subject (who was excluded), the pH in the upper esophagus remained above 5 throughout all studies. In 8 subjects, ZD6416 attenuated the reduction in PT in the upper esophagus normally induced by acid infusion into the lower esophagus (area under curve [AUC]: -11.9 +/- 2.5 and 6.4 +/- 6.7 for placebo and ZD6416, respectively; P < 0.01). After saline infusion, the effects of ZD6416 and placebo were similar (AUC: 9.9 +/- 6 and 4.1 +/- 2, respectively; P = 0.8). Three subjects had no reduction in PT to acid infusion with placebo and were excluded at post hoc analysis.

CONCLUSIONS:

The attenuation of secondary esophageal hyperalgesia by ZD6416 suggests that PGE(2), via the EP-1 receptor, contributes to human visceral pain hypersensitivity.

100 Deals associated with ZD-6416

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