Delving into the Latest Updates on PF-04363467 with Synapse

Overview

Basic Info

Drug Type

Small molecule drug

Synonyms

Target

D2 receptor x D3 receptor

Mechanism

D2 receptor antagonists(Dopamine D2 receptor antagonists), D3 receptor antagonists(Dopamine D3 receptor antagonists)

Therapeutic Areas

Other Diseases

Active Indication

Tobacco Use Disorder

Inactive Indication-

Originator Organization

Pfizer Inc.

Active Organization

Pfizer Inc.

Inactive Organization-

Drug Highest PhasePreclinical

First Approval Date-

Regulation-

Author: O’Connor, Rebecca E. ; Majchrzak, Mark J. ; Kormos, Bethany L. ; Hsu, Cathleen ; Wager, Travis T. ; Horton, David ; Stratman, Nancy C. ; Vanase-Frawley, Michelle A. ; Dunn-Sims, Elizabeth R. ; Schmidt, Christopher J. ; Sawant-Basak, Aarti ; Chappie, Thomas ; Nguyen, David P. ; Samas, Brian ; Chandrasekaran, Ramalakshmi Y. ; Mead, Andy N. ; Nawreen, Nawshaba ; Dlugolenski, Keith

Dopamine receptor antagonism is a compelling molecular target for the treatment of a range of psychiatric disorders, including substance use disorders. From our corporate compound file, we identified a structurally unique D3 receptor (D3R) antagonist scaffold, 1. Through a hybrid approach, we merged key pharmacophore elements from 1 and D3 agonist 2 to yield the novel D3R/D2R antagonist PF-4363467 (3). Compound 3 was designed to possess CNS drug-like properties as defined by its CNS MPO desirability score (≥4/6). In addition to good physicochemical properties, 3 exhibited low nanomolar affinity for the D3R (D3 K_i = 3.1 nM), good subtype selectivity over D2R (D2 K_i = 692 nM), and high selectivity for D3R versus other biogenic amine receptors. In vivo, 3 dose-dependently attenuated opioid self-administration and opioid drug-seeking behavior in a rat operant reinstatement model using animals trained to self-administer fentanyl. Further, traditional extrapyramidal symptoms (EPS), adverse side effects arising from D2R antagonism, were not observed despite high D2 receptor occupancy (RO) in rodents, suggesting that compound 3 has a unique in vivo profile. Collectively, our data support further investigation of dual D3R and D2R antagonists for the treatment of drug addiction.

100 Deals associated with PF-04363467

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