Delving into the Latest Updates on R-1487 with Synapse

Overview

Basic Info

Drug Type

Small molecule drug

Synonyms

R 1487, R1487

Target

p38α

Mechanism

p38α inhibitors(P38 α mitogen-activated protein kinase inhibitors)

Therapeutic Areas

Immune System DiseasesSkin and Musculoskeletal Diseases

Active Indication

Rheumatoid Arthritis

Inactive Indication-

Originator Organization

F. Hoffmann-La Roche Ltd.

Active Organization

Roche Palo Alto LLC

Inactive Organization

F. Hoffmann-La Roche Ltd.

Roche Holding AG

Drug Highest PhasePreclinical

First Approval Date-

Regulation-

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Structure/Sequence

Molecular FormulaC19H18F2N4O3

InChIKeyKKKRKRMVJRHDMG-UHFFFAOYSA-N

CAS Registry449811-92-1

p38α, a member of the mitogen-activated protein kinase superfamily, is activated by external stimuli, followed by nuclear translocation for the regulation of inflammatory responses at the transcriptional and translational levels in inflammatory diseases. Thus, activated p38α would be an appropriate target molecule for in vivo noninvasive imaging and targeted radionuclide therapy. For this purpose, we designed a radiobrominated compound, 6-(4-[⁷⁷Br]bromo-2-fluorophenoxy)-8-methyl-2-(tetrahydro-2H-pyran-4-ylamino)-pyrido[2,3-d]pyrimidin-7(8H)-one ([⁷⁷Br]4-BR), based on a potent p38α selective inhibitor, R1487, for use with single-photon emission computed tomography. We synthesized [⁷⁷Br]4-BR and evaluated its effectiveness as an activated p38α imaging probe compared with our previous radioiodinated probe (6-(2-fluoro-4-[¹²⁵I]iodophenoxy)-8-methyl-2-(tetrahydro-2H-pyran-4-ylamino)-pyrido[2,3-d]pyrimidin-7(8H)-one ([¹²⁵I]4-IR)) in a mouse inflammatory model.

METHODS:

We designed [⁷⁷Br]4-BR by replacing the radioiodine of [¹²⁵I]4-IR or the fluorine of R1487 with radiobromine at the 4-position of the phenoxy ring. We synthesized 4-BR via a four-step process. The inhibitory potency of 4-BR was measured using an ADP-Glo™ kinase assay system. Radiosynthesis of [⁷⁷Br]4-BR was performed via an organotin-radiobromine exchange reaction using the corresponding tributyltin precursor. Radioactivity biodistribution was evaluated in normal ddY mice and turpentine oil-induced inflammation model mice for 120 min after intravenous administration of [⁷⁷Br]4-BR. The temporal changes in radioactivity in blood fractions were compared between [⁷⁷Br]4-BR and [¹²⁵I]4-IR.

RESULTS:

4-BR was synthesized at a total yield of 9.1% and showed a p38α inhibitory potency similar to that of 4-IR. [⁷⁷Br]4-BR was successfully obtained from a tributyltin precursor with high radiochemical yield (89.9%), purity (95.9%), and molar activity (2.0 TBq/µmol). [⁷⁷Br]4-BR showed accumulation of high radioactivity in the inflamed tissue (3.4% ± 0.9% ID/g, peaking at 15 min), rapid delivery throughout the body, and rapid blood clearance with approximately half of the blood radioactivity existing as an intact form at 60 min. Although the maximum radioactivity accumulation in inflamed tissue after [⁷⁷Br]4-BR administration was approximately half that of [¹²⁵I]4-IR because of its faster blood clearance and lower free fraction in the input function, the inflamed tissue-to-blood ratio was comparable between [⁷⁷Br]4-BR and [¹²⁵I]4-IR.

CONCLUSIONS:

[⁷⁷Br]4-BR would be a promising imaging agent for detecting activated p38α in inflammatory diseases.

01 Dec 2021·Annals of nuclear medicineQ4 · MEDICINE

Development of radioiodinated pyrimidinopyridone derivatives as targeted imaging probes of activated p38α for single photon emission computed tomography

Q4 · MEDICINE

Article

Author: Hirata, Masahiko ; Temma, Takashi ; Kondo, Naoya ; Hashimoto, Tomoyuki

OBJECTIVE:

p38α, a member of the mitogen-activated protein kinase superfamily, is ubiquitously expressed in a variety of mammalian cells. Activated p38α induces inflammatory responses to external stimuli, suggesting that non-invasive detection of activated p38α would be valuable for diagnosing inflammatory diseases. For this purpose, we designed radiolabeled compounds [¹²³I]2-IR and [¹²³I]4-IR based on a potent p38α selective inhibitor R1487 for use with single photon emission computed tomography (SPECT). In this study, we used ¹²⁵I instead of ¹²³I due to its more usable radiochemical properties, synthesized [¹²⁵I]2-IR and [¹²⁵I]4-IR, and evaluated their effectiveness as activated p38α imaging probes.

METHODS:

[¹²³I]2-IR and [¹²³I]4-IR were designed by introduction of a ¹²³I atom at the 2- or 4-ositions of the phenoxy ring, preserving the pyrimidinopyridone structure of R1487. We synthesized 2-IR and 4-IR via a 7-step process. The inhibitory potencies of 2-IR, 4-IR, and p38α inhibitors were measured using an ADP-Glo™ kinase assay system. Radioiodination of 2-IR and 4-IR was performed via an organotin-radioiodine exchange reaction using the corresponding tributyltin precursors. Biodistributions were evaluated by determining radioactivity in tissues of interest after intravenous administration of [¹²⁵I]2-IR and [¹²⁵I]4-IR in normal ddY mice and turpentine oil-induced inflammation model mice. In vivo inhibition study was also performed in inflammation model mice after intravenous administration of [¹²⁵I]4-IR with pretreatment of p38α inhibitors.

RESULTS:

We synthesized 2-IR and 4-IR at total yields of 17.5% and 19.2%, respectively. 4-IR had higher p38α inhibitory potency than 2-IR; both compounds were significantly less potent than R1487. [¹²⁵I]2-IR and [¹²⁵I]4-IR were successfully obtained from tributyltin precursors with high radiochemical yield (> 65%), purity (> 97%), and molar activity (~ 81 GBq/µmol). [¹²⁵I]4-IR showed high radioactivity accumulation in the inflamed tissue (7.0 ± 1.2%D/g), rapid delivery throughout the body, and rapid blood clearance, resulting in a high inflammation-to-blood ratio (6.2 ± 0.4) and a high inflammation-to-muscle ratio (5.2 ± 1.3) at 30 min, while [¹²⁵I]2-IR showed low radioactivity accumulation in inflamed tissue over the experimental period. Further, radioactivity accumulation in inflamed tissue after [¹²⁵I]4-IR administration was significantly decreased by pretreatment with selective inhibitors.

CONCLUSIONS:

[¹²³I]4-IR would be a promising imaging agent for detection of activated p38α.

01 Oct 2012·European journal of medicinal chemistryQ1 · MEDICINE

Discovery of N6-phenyl-1H-pyrazolo[3,4-d]pyrimidine-3,6-diamine derivatives as novel CK1 inhibitors using common-feature pharmacophore model based virtual screening and hit-to-lead optimization

Q1 · MEDICINE

Article

Author: Pan Ji ; Heng-Xiu Yan ; Shan Feng ; Jun Zou ; Guo-Bo Li ; Qi-Zheng Sun ; Shuang Ma ; Ling-Ling Yang ; Sheng-Yong Yang ; Ze-Rong Wang

Aberrant activation of casein kinase 1 (CK1) has been demonstrated to be implicated in the pathogenesis of cancer and various central nervous system disorders. Discovery of CK1 inhibitors has thus attracted much attention in recent years. In this account, we describe the discovery of N6-phenyl-1H-pyrazolo[3,4-d]pyrimidine-3,6-diamine derivatives as novel CK1 inhibitors. An optimal common-feature pharmacophore hypothesis, termed Hypo2, was firstly generated, followed by virtual screening using Hypo2 against several chemical databases. One of the best hit compounds, N6-(4-chlorophenyl)-1H-pyrazolo[3,4-d]pyrimidine-3,6-diamine, was chosen for the subsequent hit-to-lead optimization under the guide of Hypo2, which led to the discovery of a new lead compound (1-(3-(3-amino-1H-pyrazolo[3,4-d]pyrimidin-6-ylamino)phenyl)-3-(3-chloro-4-fluorophenyl)urea) that potently inhibits CK1 with an IC(50) value of 78 nM.

100 Deals associated with R-1487

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