FRINK Linked Data Fragments server

Matches in SemOpenAlex for { <https://semopenalex.org/work/W2108492017> ?p ?o ?g. }

• W2108492017 endingPage "310" @default.
• W2108492017 startingPage "298" @default.
• W2108492017 abstract "The dysregulation of phosphatidylinositol 3-kinase (PI3K)-dependent pathways is implicated in several human cancers making it an attractive target for small molecule PI3K inhibitors. A series of potent pyridyltriazine-containing inhibitors of class Ia PI3Ks were synthesized and a subset of compounds was evaluated in exploratory repeat-dose rat toxicology studies. Daily oral dosing of compound 1: in Sprague Dawley rats for four consecutive days was associated with hepatobiliary toxicity that included biliary epithelial hyperplasia and hypertrophy, periductular edema, biliary stasis, and acute peribiliary inflammatory infiltrates. These histological changes were associated with clinical pathology changes that included increased serum liver enzymes, total bile acids, and bilirubin. The predominant clearance pathway of 1: was shown in vitro and in a bile-duct cannulated rat (14)C-ADME study to be P450-mediated oxidative metabolism. An O-demethylated pyridine metabolite, M3: , was identified as a candidate proximal metabolite that caused the hepatotoxicity. Co-administration of the pan-P450 inhibitor 1-aminobenzotriazole with 1: to rats significantly reduced the formation of M3: and prevented liver toxicity, whereas direct administration of M3: reproduced the toxicity. Structural changes were introduced to 1: to make the methoxypyridine ring less susceptible to P450 oxidation (compound 2: ), and addition of a methyl group to the benzylic carbon (compound 3: ) improved the pharmacokinetic profile. These changes culminated in the successful design of a clinical candidate 3: (AMG 511) that was devoid of liver toxicity in a 14-day rat toxicity study. Herein, we describe how a metabolism-based structure-activity relationship analysis allowed for the successful identification of a PI3K inhibitor devoid of off-target toxicity." @default.
• W2108492017 created "2016-06-24" @default.
• W2108492017 creator A5006276626 @default.
• W2108492017 creator A5007209676 @default.
• W2108492017 creator A5015046857 @default.
• W2108492017 creator A5019502209 @default.
• W2108492017 creator A5023640735 @default.
• W2108492017 creator A5043230719 @default.
• W2108492017 creator A5048112209 @default.
• W2108492017 creator A5049963981 @default.
• W2108492017 creator A5052868348 @default.
• W2108492017 creator A5059234004 @default.
• W2108492017 creator A5063935683 @default.
• W2108492017 creator A5076558685 @default.
• W2108492017 creator A5083438463 @default.
• W2108492017 creator A5086893634 @default.
• W2108492017 creator A5091443996 @default.
• W2108492017 date "2014-08-26" @default.
• W2108492017 modified "2023-10-12" @default.
• W2108492017 title "P450-Mediated O-Demethylated Metabolite Is Responsible for Rat Hepatobiliary Toxicity of Pyridyltriazine-Containing PI3K Inhibitors" @default.
• W2108492017 cites W1597366779 @default.
• W2108492017 cites W1977267072 @default.
• W2108492017 cites W1981811774 @default.
• W2108492017 cites W1985957029 @default.
• W2108492017 cites W1998836974 @default.
• W2108492017 cites W2015138929 @default.
• W2108492017 cites W2018153260 @default.
• W2108492017 cites W2021995068 @default.
• W2108492017 cites W2044484262 @default.
• W2108492017 cites W2060968396 @default.
• W2108492017 cites W2069562097 @default.
• W2108492017 cites W2070732456 @default.
• W2108492017 cites W2161437969 @default.
• W2108492017 cites W2161521680 @default.
• W2108492017 cites W2317579113 @default.
• W2108492017 cites W4251622665 @default.
• W2108492017 doi "https://doi.org/10.1093/toxsci/kfu178" @default.
• W2108492017 hasPubMedId "https://pubmed.ncbi.nlm.nih.gov/25159132" @default.
• W2108492017 hasPublicationYear "2014" @default.
• W2108492017 type Work @default.
• W2108492017 sameAs 2108492017 @default.
• W2108492017 citedByCount "7" @default.
• W2108492017 countsByYear W21084920172015 @default.
• W2108492017 countsByYear W21084920172018 @default.
• W2108492017 countsByYear W21084920172019 @default.
• W2108492017 countsByYear W21084920172020 @default.
• W2108492017 countsByYear W21084920172021 @default.
• W2108492017 crossrefType "journal-article" @default.
• W2108492017 hasAuthorship W2108492017A5006276626 @default.
• W2108492017 hasAuthorship W2108492017A5007209676 @default.
• W2108492017 hasAuthorship W2108492017A5015046857 @default.
• W2108492017 hasAuthorship W2108492017A5019502209 @default.
• W2108492017 hasAuthorship W2108492017A5023640735 @default.
• W2108492017 hasAuthorship W2108492017A5043230719 @default.
• W2108492017 hasAuthorship W2108492017A5048112209 @default.
• W2108492017 hasAuthorship W2108492017A5049963981 @default.
• W2108492017 hasAuthorship W2108492017A5052868348 @default.
• W2108492017 hasAuthorship W2108492017A5059234004 @default.
• W2108492017 hasAuthorship W2108492017A5063935683 @default.
• W2108492017 hasAuthorship W2108492017A5076558685 @default.
• W2108492017 hasAuthorship W2108492017A5083438463 @default.
• W2108492017 hasAuthorship W2108492017A5086893634 @default.
• W2108492017 hasAuthorship W2108492017A5091443996 @default.
• W2108492017 hasBestOaLocation W21084920171 @default.
• W2108492017 hasConcept C114246631 @default.
• W2108492017 hasConcept C126322002 @default.
• W2108492017 hasConcept C140027455 @default.
• W2108492017 hasConcept C185592680 @default.
• W2108492017 hasConcept C2777477808 @default.
• W2108492017 hasConcept C29730261 @default.
• W2108492017 hasConcept C526171541 @default.
• W2108492017 hasConcept C55493867 @default.
• W2108492017 hasConcept C62231903 @default.
• W2108492017 hasConcept C71924100 @default.
• W2108492017 hasConcept C98274493 @default.
• W2108492017 hasConceptScore W2108492017C114246631 @default.
• W2108492017 hasConceptScore W2108492017C126322002 @default.
• W2108492017 hasConceptScore W2108492017C140027455 @default.
• W2108492017 hasConceptScore W2108492017C185592680 @default.
• W2108492017 hasConceptScore W2108492017C2777477808 @default.
• W2108492017 hasConceptScore W2108492017C29730261 @default.
• W2108492017 hasConceptScore W2108492017C526171541 @default.
• W2108492017 hasConceptScore W2108492017C55493867 @default.
• W2108492017 hasConceptScore W2108492017C62231903 @default.
• W2108492017 hasConceptScore W2108492017C71924100 @default.
• W2108492017 hasConceptScore W2108492017C98274493 @default.
• W2108492017 hasIssue "1" @default.
• W2108492017 hasLocation W21084920171 @default.
• W2108492017 hasLocation W21084920172 @default.
• W2108492017 hasOpenAccess W2108492017 @default.
• W2108492017 hasPrimaryLocation W21084920171 @default.
• W2108492017 hasRelatedWork W1984754514 @default.
• W2108492017 hasRelatedWork W2007524325 @default.
• W2108492017 hasRelatedWork W2026368317 @default.
• W2108492017 hasRelatedWork W2059101420 @default.
• W2108492017 hasRelatedWork W2060888477 @default.
• W2108492017 hasRelatedWork W2068400676 @default.
• W2108492017 hasRelatedWork W2094655860 @default.

• next