Delving into the Latest Updates on Gisadenafil with Synapse

Overview

Basic Info

Drug Type

Small molecule drug

Synonyms

Gisadenafil (USAN/INN), Gisadenafil Besylate

Target

PDE5A

Mechanism

PDE5A inhibitors(Phosphodiesterase 5A inhibitors)

Therapeutic Areas

Urogenital DiseasesOther DiseasesRespiratory Diseases

Active Indication-

Inactive Indication

Erectile DysfunctionLower Urinary Tract SymptomsProstatic Hyperplasia+ [2]

Originator Organization

Pfizer Inc.

Active Organization-

Inactive Organization

Pfizer Inc.

Drug Highest PhasePendingPhase 2

First Approval Date-

Regulation-

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Structure

Molecular FormulaC23H33N7O5S

InChIKeyYPFZMBHKIVDSNR-UHFFFAOYSA-N

CAS Registry334826-98-1

AbstractBackgroundCerebral blood flow (CBF) is known to be dysregulated in persons with human immunodeficiency virus 1 (HIV-1), for uncertain reasons. This is an important issue because impaired vasoreactivity has been associated with increased risk of ischemic stroke, elevated overall cardiovascular risk and cognitive impairment.MethodsTo test whether dysregulation of CBF might be due to virally-induced neuroinflammation, we used a well-defined animal model (GFAP-driven, doxycycline-inducible HIV-1 Tat transgenic (Tat-tg) mice). We then exposed the mice to a brief hypercapnic stimulus, and assessed cerebrovascular reactivity by measuring 1) changes in cerebral blood flow, using laser Doppler flowmetry and 2) changes in vascular dilation, using in vivo two-photon imaging.ResultsExposure to brief hypercapnia revealed an underlying cerebrovascular pathology in Tat-tg mice. In control animals, brief hypercapnia induced a brisk increase in cortical flow (20.8% above baseline) and vascular dilation, as measured by laser Doppler flowmetry and in vivo two-photon microscopy. These responses were significantly attenuated in Tat-tg mice (11.6% above baseline), but cortical microvascular morphology and capillary density were unaltered, suggesting that the functional pathology was not secondary to vascular remodeling. To examine the mechanistic basis for the diminished cerebrovascular response to brief hypercapnia, Tat-tg mice were treated with 1) gisadenafil, a phosphodiesterase 5 (PDE5) inhibitor and 2) tetrahydrobiopterin (BH4). Gisadenafil largely restored the normal increase in cortical flow following hypercapnia in Tat-tg mice (17.5% above baseline), whereas BH4 had little effect. Gisadenafil also restored the dilation of small (<25 μm) arterioles following hypercapnia (19.1% versus 20.6% diameter increase in control and Tat-tg plus gisadenafil, respectively), although it failed to restore full dilation of larger (>25 μm) vessels.ConclusionsTaken together, these data show that HIV-associated neuroinflammation can cause cerebrovascular pathology through effects on cyclic guanosine monophosphate (cGMP) metabolism and possibly on PDE5 metabolism.

01 Jan 2012·Journal of UrologyQ1 · MEDICINE

Re: A Placebo-Controlled Study Investigating the Efficacy and Safety of the Phosphodiesterase Type 5 Inhibitor UK-369,003 for the Treatment of Men With Lower Urinary Tract Symptoms Associated With Clinical Benign Prostatic Hyperplasia

Q1 · MEDICINE

Article

Author: Kaplan, Steven A.

01 Jan 2012·Bioorganic & Medicinal ChemistryQ3 · MEDICINE

The discovery of UK-369003, a novel PDE5 inhibitor with the potential for oral bioavailability and dose-proportional pharmacokinetics

Q3 · MEDICINE

Article

Author: Rachel Russel ; James Gosset ; Marion Floc’h ; Graham Maw ; Stephen Denton ; William Million ; Stephen Ballard ; Mark Bunnage ; Frances Holmwood ; David Leahy ; Charlotte Lane ; David Ellis ; David J. Rawson ; Stephen Street ; Laura Barker ; Cedric Poinsard ; Laura Foster ; Susan Cole ; Christopher Barber ; Lesa Watson ; John Mathias ; Kevin Beaumont ; Jenny Price ; Martin Corless

This paper describes our recent efforts to design and synthesise potent and selective PDE5 inhibitors and the use of in vitro predictors of clearance, absorption and permeability to maximise the potential for dose-proportional pharmacokinetics and good oral bioavailability in man. Optimisation of the preclinical profile resulted in the identification of UK-369003 (19a) and its nomination as a clinical candidate. The clinical pharmacokinetic and safety profile has enabled us to progress the compound to test its efficacy in patients with lower urinary tract symptoms (LUTS) associated with benign prostatic hyperplasia (BPH) and a paper describing its efficacy has recently been published.

100 Deals associated with Gisadenafil

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External Link

KEGG	Wiki	ATC	Drug Bank
D09621	-	-	DB11902

R&D Status

10 top R&D records.

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Indication	Highest Phase	Country/Location	Organization	Date
Lower Urinary Tract Symptoms	Phase 2	SK	Pfizer Inc.	01 Mar 2007
Lower Urinary Tract Symptoms	Phase 2	NL	Pfizer Inc.	01 Mar 2007
Lower Urinary Tract Symptoms	Phase 2	CZ	Pfizer Inc.	01 Mar 2007
Erectile Dysfunction	Phase 2	-	Pfizer Inc.	01 Feb 2005
Erectile Dysfunction	Phase 2	US	Pfizer Inc.	01 Feb 2005
Pulmonary Disease, Chronic Obstructive	Phase 2	IN	Pfizer Inc.	01 Dec 2004
Pulmonary Disease, Chronic Obstructive	Phase 2	AU	Pfizer Inc.	01 Dec 2004
Pulmonary Disease, Chronic Obstructive	Phase 2	AR	Pfizer Inc.	01 Dec 2004
Pulmonary Disease, Chronic Obstructive	Phase 2	DE	Pfizer Inc.	01 Dec 2004
Pulmonary Disease, Chronic Obstructive	Discovery	GB	Pfizer Inc.	01 Dec 2004