LISOFYLLINE

Details

Stereochemistry	ABSOLUTE
Molecular Formula	C13H20N4O3
Molecular Weight	280.3229
Optical Activity	UNSPECIFIED
Defined Stereocenters	1 / 1
E/Z Centers	0
Charge	0

SHOW SMILES / InChI

Structure Search

SMILES

C[C@@H](O)CCCCN1C(=O)N(C)C2=C(N(C)C=N2)C1=O

InChI

InChIKey=NSMXQKNUPPXBRG-SECBINFHSA-N

InChI=1S/C13H20N4O3/c1-9(18)6-4-5-7-17-12(19)10-11(14-8-15(10)2)16(3)13(17)20/h8-9,18H,4-7H2,1-3H3/t9-/m1/s1

HIDE SMILES / InChI

Description
Sources: https://www.ncbi.nlm.nih.gov/pubmed/15588708 | https://www.ncbi.nlm.nih.gov/pubmed/8171002 | https://www.ncbi.nlm.nih.gov/pubmed/10586050 | http://adisinsight.springer.com/drugs/800003961

Lisofylline [1-(5R-hydroxyhexyl)-3,7-dimethylxanthine] is a unique metabolite of pentoxifylline. Lisofylline inhibited the generation of phosphatidic acid and free fatty acids. Lisofylline blocked the release of pro-inflammatory cytokines in oxidative tissue injury, in response to cancer chemotherapy and in experimental sepsis. Lisofylline regulates immune cell function and autoimmune response by inhibition of IL-12 signalling and cytokine production. Lisofylline may have therapeutic value in the prevention of autoimmune disorders, including Type 1 diabetes, autoimmune recurrence following islet transplantation, and in preservation of beta cell functional mass during islet isolation.

CNS Activity

Originator

Approval Year

Targets

Primary Target	Pharmacology	Condition	Potency
1-acylglycerol-3-phosphate O-acyltransferase alpha 1 Target ID: CHEMBL3583 Sources: https://www.ncbi.nlm.nih.gov/pubmed/8171002 \| https://www.ncbi.nlm.nih.gov/pubmed/9575575	Inhibitor 8297
1-acylglycerol-3-phosphate O-acyltransferase beta 1 Target ID: CHEMBL4772 Sources: https://www.ncbi.nlm.nih.gov/pubmed/8171002 \| https://www.ncbi.nlm.nih.gov/pubmed/9575575	Inhibitor 8297
Signal transducer and activator of transcription 4 1 Target ID: Q14765 Gene ID: 6775.0 Gene Symbol: STAT4 Target Organism: Homo sapiens (Human) Sources: https://www.ncbi.nlm.nih.gov/pubmed/10586050	Inhibitor 8297

Conditions

Condition	Modality	Targets	Highest Phase	Product
Type 1 diabetes mellitus 17 Sources: https://www.ncbi.nlm.nih.gov/pubmed/15588708	Primary		Phase II 1132	Unknown Approved Use Unknown
Transplant rejection 8 Sources: http://adisinsight.springer.com/drugs/800003961	Primary		Phase III 656	Unknown Approved Use Unknown

C_max

Value	Dose	Analyte	Population
5698 ng/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/9435196	3 mg/kg single, intravenous dose: 3 mg/kg route of administration: Intravenous experiment type: SINGLE co-administered:	LISOFYLLINE plasma	Homo sapiens population: HEALTHY age: ADULT sex: MALE food status: FED
226 ng/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/9435196	226 mg/kg single, oral dose: 226 mg/kg route of administration: Oral experiment type: SINGLE co-administered:	LISOFYLLINE plasma	Homo sapiens population: HEALTHY age: ADULT sex: MALE food status: FED
10.88 μM EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/10673700	3 mg/kg single, intravenous dose: 3 mg/kg route of administration: Intravenous experiment type: SINGLE co-administered:	LISOFYLLINE plasma	Homo sapiens population: UNHEALTHY age: ADULT sex: FEMALE / MALE food status: UNKNOWN

AUC

Value	Dose	Co-administered	Analyte	Population
2756 ng × h/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/9435196	3 mg/kg single, intravenous dose: 3 mg/kg route of administration: Intravenous experiment type: SINGLE co-administered:		LISOFYLLINE plasma	Homo sapiens population: HEALTHY age: ADULT sex: MALE food status: FED
343 ng × h/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/9435196	226 mg/kg single, oral dose: 226 mg/kg route of administration: Oral experiment type: SINGLE co-administered:		LISOFYLLINE plasma	Homo sapiens population: HEALTHY age: ADULT sex: MALE food status: FED

T_1/2

Value	Dose	Co-administered	Analyte	Population
0.77 h EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/9435196	3 mg/kg single, intravenous dose: 3 mg/kg route of administration: Intravenous experiment type: SINGLE co-administered:		LISOFYLLINE plasma	Homo sapiens population: HEALTHY age: ADULT sex: MALE food status: FED
0.9 h EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/9435196	226 mg/kg single, oral dose: 226 mg/kg route of administration: Oral experiment type: SINGLE co-administered:		LISOFYLLINE plasma	Homo sapiens population: HEALTHY age: ADULT sex: MALE food status: FED

Doses

Dose	Population	Adverse events
3 mg/kg 1 times / 6 hours multiple, intravenous Studied dose Dose: 3 mg/kg, 1 times / 6 hours Route: intravenous Route: multiple Dose: 3 mg/kg, 1 times / 6 hours Sources: https://pubmed.ncbi.nlm.nih.gov/10673700 Page: p.286	unhealthy, ADULT n = 19 Health Status: unhealthy Condition: Hematologic malignancy Age Group: ADULT Sex: M+F Food Status: UNKNOWN Population Size: 19 Sources: https://pubmed.ncbi.nlm.nih.gov/10673700 Page: p.286	Disc. AE: Feelings of weakness, Vasodilatation... AEs leading to discontinuation/dose reduction: Feelings of weakness (5.3%) Vasodilatation (5.3%) Seizures (5.3%) Nausea (10.5%) Vomiting (10.5%) Sources: https://pubmed.ncbi.nlm.nih.gov/10673700 Page: p.286

AEs

AE	Significance	Dose	Population
Nausea	10.5% Disc. AE	3 mg/kg 1 times / 6 hours multiple, intravenous Studied dose Dose: 3 mg/kg, 1 times / 6 hours Route: intravenous Route: multiple Dose: 3 mg/kg, 1 times / 6 hours Sources: https://pubmed.ncbi.nlm.nih.gov/10673700 Page: p.286	unhealthy, ADULT n = 19 Health Status: unhealthy Condition: Hematologic malignancy Age Group: ADULT Sex: M+F Food Status: UNKNOWN Population Size: 19 Sources: https://pubmed.ncbi.nlm.nih.gov/10673700 Page: p.286
Vomiting	10.5% Disc. AE	3 mg/kg 1 times / 6 hours multiple, intravenous Studied dose Dose: 3 mg/kg, 1 times / 6 hours Route: intravenous Route: multiple Dose: 3 mg/kg, 1 times / 6 hours Sources: https://pubmed.ncbi.nlm.nih.gov/10673700 Page: p.286	unhealthy, ADULT n = 19 Health Status: unhealthy Condition: Hematologic malignancy Age Group: ADULT Sex: M+F Food Status: UNKNOWN Population Size: 19 Sources: https://pubmed.ncbi.nlm.nih.gov/10673700 Page: p.286
Feelings of weakness	5.3% Disc. AE	3 mg/kg 1 times / 6 hours multiple, intravenous Studied dose Dose: 3 mg/kg, 1 times / 6 hours Route: intravenous Route: multiple Dose: 3 mg/kg, 1 times / 6 hours Sources: https://pubmed.ncbi.nlm.nih.gov/10673700 Page: p.286	unhealthy, ADULT n = 19 Health Status: unhealthy Condition: Hematologic malignancy Age Group: ADULT Sex: M+F Food Status: UNKNOWN Population Size: 19 Sources: https://pubmed.ncbi.nlm.nih.gov/10673700 Page: p.286
Seizures	5.3% Disc. AE	3 mg/kg 1 times / 6 hours multiple, intravenous Studied dose Dose: 3 mg/kg, 1 times / 6 hours Route: intravenous Route: multiple Dose: 3 mg/kg, 1 times / 6 hours Sources: https://pubmed.ncbi.nlm.nih.gov/10673700 Page: p.286	unhealthy, ADULT n = 19 Health Status: unhealthy Condition: Hematologic malignancy Age Group: ADULT Sex: M+F Food Status: UNKNOWN Population Size: 19 Sources: https://pubmed.ncbi.nlm.nih.gov/10673700 Page: p.286
Vasodilatation	5.3% Disc. AE	3 mg/kg 1 times / 6 hours multiple, intravenous Studied dose Dose: 3 mg/kg, 1 times / 6 hours Route: intravenous Route: multiple Dose: 3 mg/kg, 1 times / 6 hours Sources: https://pubmed.ncbi.nlm.nih.gov/10673700 Page: p.286	unhealthy, ADULT n = 19 Health Status: unhealthy Condition: Hematologic malignancy Age Group: ADULT Sex: M+F Food Status: UNKNOWN Population Size: 19 Sources: https://pubmed.ncbi.nlm.nih.gov/10673700 Page: p.286

Overview

CYP3A4	CYP2C9	CYP2D6	hERG
substrate 1737

OverviewOther

Other Inhibitor	Other Substrate	Other Inducer
	CYP1A2 1054 HLM 31 CYP2E1 667 CYP2A6 543

Drug as victim

Target	Modality	Activity
CYP2E1 667	substrate 3367 Sources: https://pubmed.ncbi.nlm.nih.gov/9394024/	unlikely
CYP2A6 543	substrate 3367 Sources: https://pubmed.ncbi.nlm.nih.gov/9523995/	yes [Km 38 uM]
CYP3A4 1737	substrate 3367 Sources: https://pubmed.ncbi.nlm.nih.gov/9523995/	yes [Km 603 uM]
CYP1A2 1054	substrate 3367 Sources: https://pubmed.ncbi.nlm.nih.gov/9394024/	yes
HLM 31	substrate 3367 Sources: https://pubmed.ncbi.nlm.nih.gov/8937849/	yes

PubMed

Title	Date	PubMed
Lisofylline: a potential lead for the treatment of diabetes.	2005 Jan 1	15588708
Pentoxifylline and its major oxidative metabolites exhibit different pharmacological properties.	2006 Mar 27	16545799
Pentoxifylline as an adjunct therapy in children with cerebral malaria.	2010 Dec 21	21176151

Patents

Sample Use Guides

In Vivo Use Guide

A multicenter, randomized placebo-controlled trial was performed in patients with hematologic malignancies receiving bone marrow transplantation from HLA-identical sibling donors. Patients were randomized to receive either placebo, 2 mg/kg lisofylline or 3 mg/kg lisofylline every 6 h, beginning before conditioning and continuing to day 21 or hospital discharge.

Route of Administration: Intravenous

In Vitro Use Guide

Human blood was stimulated with various endotoxin preparations, zymosan, or protein A, and the levels of secreted monokines were measured by enzyme-linked immunosorbent assay. CT-1501R (lisofylline) inhibited tumor necrosis factor alpha (TNF-alpha), interleukin 1 beta (IL-1 beta), and IL-6 release in a dose-dependent manner and was active with all stimuli tested including Salmonella and Escherichia coli-derived endotoxin, endotoxin from both rough and smooth E. coli strains, as well as zymosan and protein A. CT-1501R inhibited monokine release by approximately 50% at 200 microM and 30% at 50 microM and was independent of the relative potency of stimulus. CT-1501R also inhibited IL-1 alpha or IL-1 beta induction of either TNF-alpha or IL-1 beta and inhibited the synergistic effects of stimulation with both human IL-1 beta and murine TNF-alpha on release of human TNF-alpha. Inhibition of monokine release following stimulation with monokine(s) was, in general, greater than that achieved with lipopolysaccharide (LPS) stimulation.

Name

Type

Language

LISOFYLLINE

Official Name

English

LISOFYLLINE [MI]

Common Name

English

1H-PURINE-2,6-DIONE, 3,7-DIHYDRO-1-(5-HYDROXYHEXYL)-3,7-DIMETHYL-, (R)-

Common Name

English

LISOFYLLINE [USAN]

Common Name

English

1-[(R)-5-Hydroxyhexyl]theobromine

Systematic Name

English

lisofylline [INN]

Common Name

English

CT1501R

Code

English

LISOFYLLINE, (R)-

Common Name

English

Lisofylline [WHO-DD]

Common Name

English

PROTEC

Brand Name

English

CT-1501R

Code

English

Classification Tree Code System Code

NCI_THESAURUS

C744