Delving into the Latest Updates on PF-232798 with Synapse

Overview

Basic Info

Drug Type

Small molecule drug

Synonyms

PF 232798, PF-00232798

Target

CCR5

Action

antagonists

Mechanism

CCR5 antagonists(C-C chemokine receptor type 5 antagonists)

Therapeutic Areas

Immune System DiseasesInfectious DiseasesUrogenital Diseases+ [1]

Active Indication-

Inactive Indication

Arrhythmias, CardiacHIV Infections

Originator Organization

Pfizer Inc.

Active Organization-

Inactive Organization

Pfizer Inc.

ViiV Healthcare Ltd.

License Organization-

Drug Highest PhaseDiscontinuedPhase 2

First Approval Date-

Regulation-

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Structure/Sequence

Molecular FormulaC29H40FN5O2

InChIKeyQETUKYDWZIRTEI-QUMGSSFMSA-N

CAS Registry849753-15-7

The chemokine receptor CCR5 is an important anti-HIV (human immunodeficiency virus) drug target owning to its pivotal role in HIV-1 viral entry as a co-receptor. Here, we present a 2.9 Å resolution crystal structure of CCR5 bound to PF-232798, a second-generation oral CCR5 antagonist currently in phase II clinical trials. PF-232798 and the marketed HIV drug maraviroc share a similar tropane scaffold with different amino (N)- and carboxyl (C)- substituents. Comparison of the CCR5-PF-232798 structure with the previously determined structure of CCR5 in complex with maraviroc reveals different binding modes of the two allosteric antagonists and subsequent conformational changes of the receptor. Our results not only offer insights into the phenomenon that PF-232798 has higher affinity and alternative resistance profile to maraviroc, but also will facilitate the design of new anti-HIV drugs.

09 Sep 2014·PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA

Ligand- and mutation-induced conformational selection in the CCR5 chemokine G protein-coupled receptor

Article

Author: Trzaskowski, Bartosz ; Goddard, William A. ; Irons, Christopher ; Olave, Ivan ; Nesterov, Alexandre ; Abrol, Ravinder

Significance:

The C-C chemokine receptor type 5 (CCR5) G protein-coupled receptor (GPCR) is a prime target for preventing HIV invasion. A major difficulty in developing effective therapeutics is that the CCR5 exhibits an ensemble of ∼ 10–20 distinct low-energy conformations, each of which might favor binding to different ligands and/or lead to different downstream functions. X-ray structures generally provide only one of these conformations. We applied the GEnSeMBLE methodology to predict this ensemble, and we designed and carried out 11 experiments to validate the ability of this ensemble to predict binding of an HIV therapeutic to CCR5. We found that each of the mutations changes the binding site. The predicted effects of mutations on binding are in excellent agreement with experiments, providing CCR5 structures for designing new ligands.

13 Jan 2011·Journal of medicinal chemistryQ1 · MEDICINE

An Imidazopiperidine Series of CCR5 Antagonists for the Treatment of HIV: The Discovery of N-{(1S)-1-(3-Fluorophenyl)-3-[(3-endo)-3-(5-isobutyryl-2-methyl-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridin-1-yl)-8-azabicyclo[3.2.1]oct-8-yl]propyl}acetamide (PF-232798)

Q1 · MEDICINE

Article

Author: Smith, Nicholas N. ; Fenwick, David R. ; Dorr, Patrick K. ; Pryde, David C. ; Stupple, Paul A. ; Ellis, David ; Platts, Michelle Y. ; Webster, Robert ; Batchelor, David V. ; Mason, Helen J. ; Perros, Manos ; Rodrigues, Deborah ; Galan, Sébastien R. G. ; Perruccio, Francesca ; Corless, Martin ; Westby, Mike ; Jones, Rhys M. ; Stephenson, Peter T. ; Middleton, Donald S. ; Wood, Anthony

Preventing entry of HIV into human host cells has emerged as an attractive approach to controlling viral replication. Maraviroc 1 is an approved antagonist of the human CCR5 receptor which prevents the entry of HIV. Herein, we report the design and discovery of a series of imidazopiperidine CCR5 antagonists which retain the attractive antiviral profile and window over hERG activity of maraviroc 1, combined with improved absorption profiles in rat and dog. Furthermore, this series of compounds has been shown to retain activity against a laboratory generated maraviroc-resistant HIV-1 strain, which indicates an alternative resistance profile to that of maraviroc 1. Compound 41f (PF-232798) was selected as a clinical candidate from the imidazopiperidine series and is currently in phase II clinical trials.

100 Deals associated with PF-232798

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External Link

KEGG	Wiki	ATC	Drug Bank
-	-	-	DB14813

R&D Status

10 top R&D records.

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Indication	Highest Phase	Country/Location	Organization	Date
HIV Infections	Phase 2	Germany	Pfizer Inc.	01 Jun 2007
Arrhythmias, Cardiac	Phase 1	Singapore	ViiV Healthcare Ltd.	01 Jul 2010
Arrhythmias, Cardiac	Phase 1	Singapore	Pfizer Inc.	01 Jul 2010

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Clinical Result

Indication

Phase

Evaluation

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Study	Phase	Population	Analyzed Enrollment	Group	Results	Evaluation	Publication Date


NCT00495677 (CTgov)	Phase 2	HIV Infections	43	PF-00232798 (PF-00232798 5 mg)	nqyomdvlxd(uvdssmqvhr) = gyekopqdrw joahxfdjzp (mqjhmlglgr, 0.3075) View more	-	30 Oct 2013
				PF-00232798 (PF-00232798 20 mg)	nqyomdvlxd(uvdssmqvhr) = hfuysnihjv joahxfdjzp (mqjhmlglgr, 0.4753) View more