Preclinical assessment of the ADME, efficacy and drug-drug interaction potential of a novel NAMPT inhibitor
GNE-617 (N-(4-((3,5-difluorophenyl)sulfonyl)benzyl)imidazo[1,2-a]pyridine-6-carboxamide) is a potent, selective nicotinamide phosphoribosyltransferase (NAMPT) inhibitor being explored as a potential treatment for human cancers. Plasma clearance was low in monkeys and dogs (9.14 mL min-1 kg-1 and 4.62 mL min-1 kg-1, respectively) and moderate in mice and rats (36.4 mL min-1 kg-1 and 19.3 mL min-1 kg-1, respectively). Oral bioavailability in mice, rats, monkeys and dogs was 29.7, 33.9, 29.4 and 65.2%, respectively. Allometric scaling predicted a low clearance of 3.3 mL min-1 kg-1 and a volume of distribution of 1.3 L kg-1 in human. Efficacy (57% tumor growth inhibition) in Colo-205 CRC tumor xenograft mice was observed at an oral dose of 15 mg/kg BID (AUC = 10.4 µM h). Plasma protein binding was moderately high. GNE-617 was stable to moderately stable in vitro. Main human metabolites identified in human hepatocytes were formed primarily by CYP3A4/5. Transporter studies suggested that GNE-617 is likely a substrate for MDR1 but not for BCRP. Simcyp® simulations suggested a low (CYP2C9 and CYP2C8) or moderate (CYP3A4/5) potential for drug-drug interactions. The potential for autoinhibition was low. Overall, GNE-617 exhibited acceptable preclinical properties and projected human PK and dose estimates.
| Medienart: |
E-Artikel |
|---|
| Erscheinungsjahr: |
2019 |
|---|---|
| Erschienen: |
2019 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:49 |
|---|---|
| Enthalten in: |
Xenobiotica; the fate of foreign compounds in biological systems - 49(2019), 9 vom: 18. Sept., Seite 1063-1077 |
| Sprache: |
Englisch |
|---|
| Beteiligte Personen: |
Liederer, Bianca M [VerfasserIn] |
|---|
| Links: |
|---|
| Anmerkungen: |
Date Completed 12.12.2019 Date Revised 17.12.2019 published: Print-Electronic Citation Status MEDLINE |
|---|
| doi: |
10.1080/00498254.2018.1528407 |
|---|
| funding: |
|
|---|---|
| Förderinstitution / Projekttitel: |
|
| PPN (Katalog-ID): |
NLM288935640 |
|---|
| LEADER | 01000naa a22002652 4500 | ||
|---|---|---|---|
| 001 | NLM288935640 | ||
| 003 | DE-627 | ||
| 005 | 20231225061438.0 | ||
| 007 | cr uuu---uuuuu | ||
| 008 | 231225s2019 xx |||||o 00| ||eng c | ||
| 024 | 7 | |a 10.1080/00498254.2018.1528407 |2 doi | |
| 028 | 5 | 2 | |a pubmed24n0963.xml |
| 035 | |a (DE-627)NLM288935640 | ||
| 035 | |a (NLM)30257601 | ||
| 040 | |a DE-627 |b ger |c DE-627 |e rakwb | ||
| 041 | |a eng | ||
| 100 | 1 | |a Liederer, Bianca M |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a Preclinical assessment of the ADME, efficacy and drug-drug interaction potential of a novel NAMPT inhibitor |
| 264 | 1 | |c 2019 | |
| 336 | |a Text |b txt |2 rdacontent | ||
| 337 | |a ƒaComputermedien |b c |2 rdamedia | ||
| 338 | |a ƒa Online-Ressource |b cr |2 rdacarrier | ||
| 500 | |a Date Completed 12.12.2019 | ||
| 500 | |a Date Revised 17.12.2019 | ||
| 500 | |a published: Print-Electronic | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a GNE-617 (N-(4-((3,5-difluorophenyl)sulfonyl)benzyl)imidazo[1,2-a]pyridine-6-carboxamide) is a potent, selective nicotinamide phosphoribosyltransferase (NAMPT) inhibitor being explored as a potential treatment for human cancers. Plasma clearance was low in monkeys and dogs (9.14 mL min-1 kg-1 and 4.62 mL min-1 kg-1, respectively) and moderate in mice and rats (36.4 mL min-1 kg-1 and 19.3 mL min-1 kg-1, respectively). Oral bioavailability in mice, rats, monkeys and dogs was 29.7, 33.9, 29.4 and 65.2%, respectively. Allometric scaling predicted a low clearance of 3.3 mL min-1 kg-1 and a volume of distribution of 1.3 L kg-1 in human. Efficacy (57% tumor growth inhibition) in Colo-205 CRC tumor xenograft mice was observed at an oral dose of 15 mg/kg BID (AUC = 10.4 µM h). Plasma protein binding was moderately high. GNE-617 was stable to moderately stable in vitro. Main human metabolites identified in human hepatocytes were formed primarily by CYP3A4/5. Transporter studies suggested that GNE-617 is likely a substrate for MDR1 but not for BCRP. Simcyp® simulations suggested a low (CYP2C9 and CYP2C8) or moderate (CYP3A4/5) potential for drug-drug interactions. The potential for autoinhibition was low. Overall, GNE-617 exhibited acceptable preclinical properties and projected human PK and dose estimates | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Video-Audio Media | |
| 650 | 4 | |a NAMPT | |
| 650 | 4 | |a allometry | |
| 650 | 4 | |a distribution | |
| 650 | 4 | |a drug-drug interactions | |
| 650 | 4 | |a efficacy | |
| 650 | 4 | |a human prediction | |
| 650 | 4 | |a metabolism | |
| 650 | 4 | |a pharmacokinetics | |
| 650 | 7 | |a Antineoplastic Agents |2 NLM | |
| 650 | 7 | |a Cytokines |2 NLM | |
| 650 | 7 | |a GNE-617 |2 NLM | |
| 650 | 7 | |a Heterocyclic Compounds, 2-Ring |2 NLM | |
| 650 | 7 | |a Sulfones |2 NLM | |
| 650 | 7 | |a Cytochrome P-450 Enzyme System |2 NLM | |
| 650 | 7 | |a 9035-51-2 |2 NLM | |
| 650 | 7 | |a Nicotinamide Phosphoribosyltransferase |2 NLM | |
| 650 | 7 | |a EC 2.4.2.12 |2 NLM | |
| 650 | 7 | |a nicotinamide phosphoribosyltransferase, human |2 NLM | |
| 650 | 7 | |a EC 2.4.2.12 |2 NLM | |
| 700 | 1 | |a Cheong, Jonathan |e verfasserin |4 aut | |
| 700 | 1 | |a Chou, Kang-Jye |e verfasserin |4 aut | |
| 700 | 1 | |a Dragovich, Peter S |e verfasserin |4 aut | |
| 700 | 1 | |a Le, Hoa |e verfasserin |4 aut | |
| 700 | 1 | |a Liang, Xiaorong |e verfasserin |4 aut | |
| 700 | 1 | |a Ly, Justin |e verfasserin |4 aut | |
| 700 | 1 | |a Mukadam, Sophie |e verfasserin |4 aut | |
| 700 | 1 | |a Oeh, Jason |e verfasserin |4 aut | |
| 700 | 1 | |a Sampath, Deepak |e verfasserin |4 aut | |
| 700 | 1 | |a Wang, Leslie |e verfasserin |4 aut | |
| 700 | 1 | |a Wong, Susan |e verfasserin |4 aut | |
| 773 | 0 | 8 | |i Enthalten in |t Xenobiotica; the fate of foreign compounds in biological systems |d 1971 |g 49(2019), 9 vom: 18. Sept., Seite 1063-1077 |w (DE-627)NLM000064742 |x 1366-5928 |7 nnns |
| 773 | 1 | 8 | |g volume:49 |g year:2019 |g number:9 |g day:18 |g month:09 |g pages:1063-1077 |
| 856 | 4 | 0 | |u http://dx.doi.org/10.1080/00498254.2018.1528407 |3 Volltext |
| 912 | |a GBV_USEFLAG_A | ||
| 912 | |a GBV_NLM | ||
| 951 | |a AR | ||
| 952 | |d 49 |j 2019 |e 9 |b 18 |c 09 |h 1063-1077 | ||