Delving into the Latest Updates on FG-2216 with Synapse

Overview

Basic Info

Drug Type

Small molecule drug

Synonyms

(((1-Chloro-4-hydroxyisoquinolin-3-yl)carbonyl)amino)acetic acid, 1-Chloro-N- (hydroxyformylmethyl-4-hydroxyisoquinoline-3-carboxamide, 1-Chloro-N-(hydroxyformylmethyl-4-hydroxyisoquinoline-3-carboxamide

+ [3]

Target

HIF-1α x PHD2

Action

inhibitors

Mechanism

HIF-1α inhibitors(Hypoxia-inducible factor 1 alpha inhibitors), PHD2 inhibitors(egl-9 family hypoxia inducible factor 1 inhibitors)

Therapeutic Areas

Hemic and Lymphatic Diseases

Active Indication-

Inactive Indication

AnemiaAnemia of renal disease

Originator Organization

Astellas Pharma, Inc.

Active Organization-

Inactive Organization

FibroGen, Inc.

Astellas Pharma, Inc.

License Organization

Astellas Pharma, Inc.

FibroGen, Inc.Yamanouchi Pharmaceutical Co., Ltd.

Drug Highest PhaseDiscontinuedPhase 2

First Approval Date-

Regulation-

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Structure/Sequence

Molecular FormulaC12H9ClN2O4

InChIKeyOUQVKRKGTAUJQA-UHFFFAOYSA-N

CAS Registry223387-75-5

Inhibition of the hypoxia-inducible factor prolyl hydroxylase (HIF-PHD) represents a promising strategy for discovering next-generation treatments for renal anemia. We identified a pyrimidine core with HIF-PHD inhibitory activity based on scaffold hopping of FG-2216 using crystal structures of HIF-PHD2 in complex with compound. By optimizing the substituents at the 2- and 6- positions of the pyrimidine core, we discovered DS44470011, which improves the effectiveness of erythropoietin (EPO) release in cells. Oral administration of DS44470011 to cynomolgus monkeys increased plasma EPO levels.

13 Jun 2024·Journal of Medicinal Chemistry

Nonclassical Zwitterions as a Design Principle to Reduce Lipophilicity without Impacting Permeability

Article

Author: Rodde, Stephane ; Strang, Ross ; Dittrich, Birger ; Möbitz, Henrik

The ionization of bioactive molecules impacts many ADME-relevant physicochemical properties, in particular, solubility, lipophilicity, and permeability. Ampholytes contain both acidic and basic groups and are distinguished as ordinary ampholytes and zwitterions. An influential review states that zwitterions only exist if the acidic pK_a is significantly lower than the basic pK_a. Through concordance of measured and calculated pK_a and log P, we show that the zwitterionic behavior of several marketed drugs and natural products occurs despite a low or negative ΔpK_a. These nonclassical zwitterions are characterized by a weak acidic and basic pK_a and conjugation through an extended aromatic system, often including pseudorings via intramolecular hydrogen bonds. In contrast to most classical zwitterions, nonclassical zwitterions can exhibit excellent permeability. As permeability and lipophilicity are typically correlated, the combination of low lipophilicity and high permeability makes nonclassical zwitterions an attractive design principle in medicinal chemistry.

28 Mar 2024·Journal of Medicinal ChemistryQ1 · MEDICINE

Focused Screening Identifies Different Sensitivities of Human TET Oxygenases to the Oncometabolite 2-Hydroxyglutarate

Q1 · MEDICINE

Article

Author: Szykowska, Aleksandra ; Salah, Eidarus ; Schofield, Christopher J. ; Burgess-Brown, Nicola ; Bhushan, Bhaskar ; Kriaucionis, Skirmantas ; Kawamura, Akane ; Belle, Roman ; Saraç, Hilal ; Tumber, Anthony ; Brown, Tom ; Roper, Grace

Ten-eleven translocation enzymes (TETs) are Fe(II)/2-oxoglutarate (2OG) oxygenases that catalyze the sequential oxidation of 5-methylcytosine to 5-hydroxymethylcytosine, 5-formylcytosine, and 5-carboxylcytosine in eukaryotic DNA. Despite their roles in epigenetic regulation, there is a lack of reported TET inhibitors. The extent to which 2OG oxygenase inhibitors, including clinically used inhibitors and oncometabolites, modulate DNA modifications via TETs has been unclear. Here, we report studies on human TET1-3 inhibition by a set of 2OG oxygenase-focused inhibitors, employing both enzyme-based and cellular assays. Most inhibitors manifested similar potencies for TET1-3 and caused increases in cellular ^5hmC levels. (R)-2-Hydroxyglutarate, an oncometabolite elevated in isocitrate dehydrogenase mutant cancer cells, showed different degrees of inhibition, with TET1 being less potently inhibited than TET3 and TET2, potentially reflecting the proposed role of TET2 mutations in tumorigenesis. The results highlight the tractability of TETs as drug targets and provide starting points for selective inhibitor design.

1

News (Medical) associated with FG-2216

04 May 2006

·www.pharmatimes.com

Astellas in mega deal for oral EPO rivals

Japanese drugmaker Astellas has licensed exclusive rights to a series of anaemia drugs from FibroGen, in a deal that could eventually bring in up to $2 billion to the US firm in the coming years. Astellas had previously licensed Japanese rights to the drugs, known as hypoxia-inducible factor prolyl hydroxylase inhibitors, but in the latest agreement has extended its rights to include Europe, the Commonwealth of Independent States, the Middle East and South Africa. The deal includes FG-2216 and FG-4592, which are currently in human clinical trials, with FibroGen retaining rights to compounds in the rest of the world. Under the terms of the agreement, Astellas will pay a licensing fee of $300 million upon signing, milestones totaling $465 million and share in the costs of a transatlantic development programme and patent support. If all forecast sales targets are achieved, FibroGen could receive in excess of $2 billion during the 10 to 15 years after 2010. In addition, Astellas will purchase $50 million worth of shares in the US biotechnology firm. The oral compounds inhibit the enzyme that degrades erythropoietin, and could be a more patient-friendly therapy option for anaemia, which is currently treated with injectable recombinant forms of EPO such as Amgen’s Epogen (epoetin alfa) and Aranesp (darbepoetin alfa), as well as Roche’s NeoRecormon (epoetin beta). Together these drugs account for a multibillion dollar market worldwide. For example, in Europe, sales of EPO products for anaemia of chronic kidney disease and chemotherapy-induced anaemia total approximately $3 billion a year. Astellas noted that oral treatments to stimulate red blood cell production could address larger, multi-million patient market opportunities currently not penetrated by EPO products, including chronic kidney disease in patients not yet on dialysis and anaemias caused by cancer, congestive heart failure, advancing age and chronic disease. Sales potential Astellas said it plans to start marketing the agents in 2011-2012, and predicts that the drugs have an annual sales potential in Europe of around 50 billion yen (roughly $450 million), which could double at peak. A launch in Japan should occur a little later, and Astellas said the market potential there is in the region of 30-50 billion yen.

100 Deals associated with FG-2216

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External Link

KEGG	Wiki	ATC	Drug Bank
-	-	-	DB08687

R&D Status

10 top R&D records.

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Indication	Highest Phase	Country/Location	Organization	Date
Anemia of renal disease	Phase 2	United States	FibroGen, Inc.	01 Dec 2005
Anemia	Phase 2	United States	Astellas Pharma, Inc.	-
Anemia	Phase 2	Europe	Astellas Pharma, Inc.	-