Preclinical toxicity and pharmacokinetics of the Bruton's tyrosine kinase-targeting anti-leukemic drug candidate, alpha-cyano-beta-hydroxy-beta-methyl-N- (2,5-dibromophenyl) propenamide (LFM-A13).
The leflunomide (CAS 75706-12-6) metabolite (LFM) analog alpha-cyano-beta-hydroxy-beta-methyl-N-(2,5-dibromophenyl)-propenamide (LFM-A13, DDE-28, CAS 244240-24-2) is a rationally-designed specific inhibitor of the TEC family protein tyrosine kinase, Bruton's tyrosine kinase (BTK). LFM-A13 exhibited favorable pharmacokinetics in CD-1 mice, BALB/c mice, rats, and dogs. The intraperitoneal bioavailability was estimated to be -100%, while the oral bioavailability was -30%. LFM-A13 enters, but does not bind to multiple tissues followed by a rapid elimination from most of the tissues. Limited distribution of LFM-A13 to extravascular tissues and its corresponding low volume of distribution could be attributed to its plasma protein binding. LFM-A13 was not toxic to mice, rats, or dogs at daily dose levels as high as 100 mg/kg. LFM-A13 formulated as a suspension and hard gelatin capsules for oral administration showed a rapid absorption and favorable pharmacokinetic features. These preclinical research studies provide the basis for future pre-IND studies and clinicaldevelopment of LFM-A13 as an intravenously or orally administered new anti-leukemia agent targeting BTK.
Uckun
Fatih M
FM
Paradigm Pharmaceuticals, 2139 Fourth Street, White Bear Lake, MN 55110, USA. faith_uckun@tmo.blackberry.net
Tibbles
Heather
H
Venkatachalam
Taracad
T
DuMez
Darin
D
Erbeck
Douglas
D
D000077329:Agammaglobulinaemia Tyrosine Kinase; D000577:Amides / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000633:toxicity*; D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000633:toxicity*; D002214:Capsules; D002851:Chromatography, High Pressure Liquid; D004285:Dogs; D005079:Excipients; D005260:Female; D005780:Gelatin; D007275:Injections, Intravenous; D007408:Intestinal Absorption; D007938:Leukemia / Q000188:drug therapy; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D009570:Nitriles / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000633:toxicity*; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors*; D051381:Rats; D011917:Rats, Inbred Lew; D013535:Suspensions; D014018:Tissue Distribution
D000577:Amides; D000970:Antineoplastic Agents; D002214:Capsules; D005079:Excipients; C118451:LFM A13; D009570:Nitriles; D013535:Suspensions; D005780:Gelatin; D011505:Protein-Tyrosine Kinases; D000077329:Agammaglobulinaemia Tyrosine Kinase; C000625951:Btk protein, mouse