Cudetaxestat (BLD-0409) CAS No.:1782070-21-6 cog lus tshuaj uas muaj peev xwm tseem ceeb hauv kev tawm tsam IPF

Cudetaxestat (BLD-0409) yog lub qhov ncauj me me molecule tsom rau lub enzyme autotaxin (ATX) los ntawm kev tsis sib haum xeeb inhibition. ATX yog ib qho enzyme secreted uas ua rau feem ntau ntawm cov lysophosphatidic acid (LPA). Kev ua haujlwm ATX nce ntxiv thiab LPA ntau dhau ua rau muaj ntau yam tsis zoo ntawm pathophysiologic phenomenon suav nrog kev ua kom myofibroblast. Activated myofibroblasts secrete extracellular matrix proteins uas sib sau ua ke rau hauv cov kab mob fibrotic. Hauv kev tshawb fawb preclinical, cudetaxestat tau qhia ncaj qha los tiv thaiv fibrotic kev ua haujlwm thiab sib txawv ntawm cov yam ntxwv biochemical.

Cudetaxestat tsis yog ib qho substrate los yog ib qho inhibitor ntawm P-gp ntawm lub cev muaj feem cuam tshuam nrog cov concentrations. Tsis muaj kev hloov pauv loj hauv plasma concentration ntawm nintedanib tau pom thaum cudetaxestat tau koom nrog hauv cov nas.

Cudetaxestat yog ib qho tsis muaj zog P-gp inhibitor thaum twg quinidine lossis nintedanib siv los ua substrate.Cudetaxestat tsis hloov pauv nintedanib raug thaum co-dosed hauv vivo hauv nas.

Taw qhia: Cudetaxestat yog qhov sib txawv, tsis sib tw me me-molecule inhibitor ntawm autotaxin tau tsim los ua kev kho qhov ncauj txhua hnub rau idiopathic pulmonary fibrosis (IPF), kab mob sclerosis-interstitial ntsws (SSc-ILD) thiab lwm yam kab mob fibrotic.
Cov txheej txheem: Lub roj teeb ntawm preclinical hauv vitro thiab ex vivo biochemical kev soj ntsuam, nrog rau cov tshuaj pharmacokinetic (PK) thiab kev tshawb fawb tshuaj (mob bleomycin qauv), tau pib ua los ntsuas lub zog thiab kev ua haujlwm ntawm cudetaxestat. Plaub Phase 1 cov kev tshawb fawb nrog cov neeg ua haujlwm pab dawb noj qab haus huv (N=216) tau ua tiav los ntsuas kev nyab xeeb / kam rau ua nrog rau PK thiab cov tshuaj pharmacodynamic (PD). Cov no suav nrog ob qhov muag tsis pom kev, placebo-tswj SAD/MAD txoj kev tshawb fawb [NCT04146805]; ib tug txheeb ze bioavailability kawm [NCT04814472]; CYP substrate kev kawm sib cuam tshuam [NCT04814498]; thiab kev sib cuam tshuam tshuaj-tshuaj (DDI) nrog kev pom zoo tus qauv kev saib xyuas (SOC) kev kho mob (nintedanib lossis pirfenidone) rau IPF [NCT04939467]. Cov txiaj ntsig: Cudetaxestat khaws cia muaj zog tiv thaiv nws lub hom phiaj hauv vitro tsis hais txog ntawm substrate concentration. Nws pom tau tias muaj kev tiv thaiv fibrotic tseem ceeb hauv ntau yam hauv vivo preclinical qauv. Plasma LPA (C18: 2) qib tau ntsuas hauv SAD / MAD txoj kev tshawb fawb thiab cov koob tshuaj nce ntxiv ua rau muaj kev txo qis LPA ntau dua thoob plaws 24- teev sijhawm noj. Thaum muab tshuaj sib xyaw nrog nintedanib lossis pirfenidone, tag nrho raug rau txhua tus ntawm cov kev kho SOC no tsis tau hloov pauv ntau. Tsis muaj cov xwm txheej tsis zoo cuam tshuam txog tshuaj (SAE's) hauv ib qho ntawm plaub theem 1 kev sim tib neeg.

Cov ntsiab lus: Cudetaxestat yog qhov muaj peev xwm ua ntej hauv chav kawm, tsis sib tw (allosteric) autotaxin inhibitor nrog cov tshuaj tiv thaiv kab mob preclinical thiab zoo PK / PD kev sib raug zoo hauv Phase 1 kev sim tshuaj. Lub cev ntawm cov ntaub ntawv no muab cov ntsiab lus ntawm koob tshuaj rau Theem 2 kev kho mob ntawm cudetaxestat hauv IPF nrog lossis tsis muaj SOC.