Olorofim

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National Institutes of Health Divider Arrow

NCATS

Details

Stereochemistry	ACHIRAL
Molecular Formula	C28H27FN6O2
Molecular Weight	498.5514
Optical Activity	NONE
Defined Stereocenters	0 / 0
E/Z Centers	0
Charge	0

SHOW SMILES / InChI

Structure of Olorofim

Structure Search

SMILES

CN1C(C)=CC(=C1C(=O)C(=O)NC2=CC=C(C=C2)N3CCN(CC3)C4=NC=C(F)C=N4)C5=CC=CC=C5

InChI

InChIKey=SUFPWYYDCOKDLL-UHFFFAOYSA-N

InChI=1S/C28H27FN6O2/c1-19-16-24(20-6-4-3-5-7-20)25(33(19)2)26(36)27(37)32-22-8-10-23(11-9-22)34-12-14-35(15-13-34)28-30-17-21(29)18-31-28/h3-11,16-18H,12-15H2,1-2H3,(H,32,37)

HIDE SMILES / InChI

Molecular Formula	C28H27FN6O2
Molecular Weight	498.5514
Charge	0
Count

Stereochemistry	ACHIRAL
Additional Stereochemistry	No
Defined Stereocenters	0 / 0
E/Z Centers	0
Optical Activity	NONE

Description
Sources: https://www.ncbi.nlm.nih.gov/pubmed/27791100/ | https://adisinsight.springer.com/drugs/800040671

F-901318 (Olorofim) is an orotomide antifungal drug. An investigation into the mechanism of action of F-901318 found that it acts via inhibition of the pyrimidine biosynthesis enzyme dihydroorotate dehydrogenase (DHODH) in a fungal-specific manner. Olorofim is being developed by F2G for the treatment of mycoses.

Originator

Approval Year

PubMed

PubMed

Title	Date	PubMed

Sample Use Guides

In Vivo Use Guide

Phase II study: 30mg with a maximum daily dose of 300mg

Route of Administration: Oral

In Vitro Use Guide

The antifungal effects of F901318 against Aspergillus fumigatus were investigated. Live cell imaging revealed that, at a concentration of 0.1 μg/ml, F901318 completely inhibited germination, but conidia continued to expand by isotropic growth for >120 h. When this low F901318 concentration was applied to germlings or vegetative hyphae, their elongation was completely inhibited within 10 h.

Substance Class	Chemical Created by `admin` on `Sat Dec 16 11:48:59 GMT 2023` Edited by `admin` on `Sat Dec 16 11:48:59 GMT 2023`
Record UNII	T34SH2H9HI
Record Status	`Validated (UNII)`
Record Version

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Name

Type

Language

Olorofim

Official Name

English

OLOROFIM [USAN]

Common Name

English

1H-Pyrrole-2-acetamide, N-[4-[4-(5-fluoro-2-pyrimidinyl)-1-piperazinyl]phenyl]-1,5-dimethyl-α-oxo-3-phenyl-

Systematic Name

English

2-(1,5-Dimethyl-3-phenyl-1H-pyrrol-2-yl)-N-{4-[4-(5-fluoropyrimidin-2-yl)piperazin-1-yl]phenyl}-2-oxoacetamide

Systematic Name

English

Olorofim [WHO-DD]

Common Name

English

F-901318

Code

English

olorofim [INN]

Common Name

English

F901318

Code

English

Classification Tree Code System Code

FDA ORPHAN DRUG

721719

Created by admin on Sat Dec 16 11:49:00 GMT 2023 , Edited by admin on Sat Dec 16 11:49:00 GMT 2023

EU-Orphan Drug

EU/3/16/1738

Created by admin on Sat Dec 16 11:49:00 GMT 2023 , Edited by admin on Sat Dec 16 11:49:00 GMT 2023

FDA ORPHAN DRUG

829821

Created by admin on Sat Dec 16 11:49:00 GMT 2023 , Edited by admin on Sat Dec 16 11:49:00 GMT 2023

FDA ORPHAN DRUG

704219

Created by admin on Sat Dec 16 11:49:00 GMT 2023 , Edited by admin on Sat Dec 16 11:49:00 GMT 2023

FDA ORPHAN DRUG

814021

Created by admin on Sat Dec 16 11:49:00 GMT 2023 , Edited by admin on Sat Dec 16 11:49:00 GMT 2023

FDA ORPHAN DRUG

702219

Created by admin on Sat Dec 16 11:49:00 GMT 2023 , Edited by admin on Sat Dec 16 11:49:00 GMT 2023

Code System Code Type Description

USAN

KL-204

Created by admin on Sat Dec 16 11:49:00 GMT 2023 , Edited by admin on Sat Dec 16 11:49:00 GMT 2023

PRIMARY

DRUG BANK

DB15245

Created by admin on Sat Dec 16 11:49:00 GMT 2023 , Edited by admin on Sat Dec 16 11:49:00 GMT 2023

PRIMARY

SMS_ID

100000181846

Created by admin on Sat Dec 16 11:49:00 GMT 2023 , Edited by admin on Sat Dec 16 11:49:00 GMT 2023

PRIMARY

INN

10648

Created by admin on Sat Dec 16 11:49:00 GMT 2023 , Edited by admin on Sat Dec 16 11:49:00 GMT 2023

PRIMARY

EU-Orphan Drug

EU/3/16/1713(POSITIVE)

Created by admin on Sat Dec 16 11:49:00 GMT 2023 , Edited by admin on Sat Dec 16 11:49:00 GMT 2023

PRIMARY

On 29 August 2016, orphan designation (EU/3/16/1713) was granted by the European Commission to F2G Ltd, United Kingdom, for 2-(1,5-dimethyl-3-phenyl-1H-pyrrol-2-yl)-N-{4-[4-(5-fluoro-pyrimidin-2-yl)piperazin-1-yl]-phenyl}-2-oxo-acetamide (also known as F901318) for the treatment of scedosporiosis.

EU-Orphan Drug

EU/3/16/1738(POSITIVE)

Created by admin on Sat Dec 16 11:49:00 GMT 2023 , Edited by admin on Sat Dec 16 11:49:00 GMT 2023

PRIMARY

On 14 October 2016, orphan designation (EU/3/16/1738) was granted by the European Commission to F2G Ltd, United Kingdom, for 2-(1,5-dimethyl-3-phenyl-1H-pyrrol-2-yl)-N-{4-[4-(5-fluoro-pyrimidin-2-yl)piperazin-1-yl]-phenyl}-2-oxo-acetamide (also known as F901318) for the treatment of invasive aspergillosis.

PUBCHEM

91885568

Created by admin on Sat Dec 16 11:49:00 GMT 2023 , Edited by admin on Sat Dec 16 11:49:00 GMT 2023

PRIMARY

NCI_THESAURUS

C170250

Created by admin on Sat Dec 16 11:49:00 GMT 2023 , Edited by admin on Sat Dec 16 11:49:00 GMT 2023

PRIMARY

FDA UNII

T34SH2H9HI

Created by admin on Sat Dec 16 11:49:00 GMT 2023 , Edited by admin on Sat Dec 16 11:49:00 GMT 2023

PRIMARY

CAS

1928707-56-5

Created by admin on Sat Dec 16 11:49:00 GMT 2023 , Edited by admin on Sat Dec 16 11:49:00 GMT 2023

PRIMARY

Related Record Type Details


					3J888Y9L13

ASPERGILLUS FLAVUS

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Amount:


					X88DF51T48

ASPERGILLUS FUMIGATUS

TARGET ORGANISM->INHIBITOR

Amount:


					242A53RB80

ASPERGILLUS NIDULANS

TARGET ORGANISM->INHIBITOR

Amount:

Related Record Type Details


					T34SH2H9HI

Olorofim

ACTIVE MOIETY

Comments:

Results: DHODH, an important enzyme in pyrimidine biosynthesis, was identified as the target of F901318 from a screen employing an Aspergillus nidulansgenomic library carried on an AMA plasmid. AMA transformants overexpressing DHODH were shown to be resistant to F901318. Knockout of the DHODH gene on the AMA plasmid restored sensitivity to F901318. Attempts to obtain mutants resistant to F901318 by repeated passage in the presence of drug failed. The antifungal action of F901318 in vitro is reversed by the addition of high concentrations of pyrimidines (circa 5mM, compared to a human serum concentration of 15 uM) confirming that the pyrimidine biosynthesis pathway is targeted in the whole cell. Inhibition of DHODH causes rapid cessation of fungal growth, and F901318 is a potent, competitive, reversible inhibitor of the recombinant Aspergillus fumigatus protein in vitro: IC50 = 44 nM +/- 10 nM (+/- standard deviation n=11). The enzyme is also present in mammalian cells but F901318 is a very poor inhibitor of the human form of the enzyme (IC50 > 90 uM) giving a >2000 fold degree of selectivity.

Amount: