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).

Abstract	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.
Authors	Fatih M Uckun, Heather Tibbles, Taracad Venkatachalam, Darin DuMez, Douglas Erbeck
Journal	Arzneimittel-Forschung (Arzneimittelforschung) Vol. 57 Issue 1 Pg. 31-46 ( 2007) ISSN: 0004-4172 [Print] Germany
PMID	17341007 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)
Chemical References	Amides Antineoplastic Agents Capsules Excipients LFM A13 Nitriles Suspensions Gelatin Protein-Tyrosine Kinases Agammaglobulinaemia Tyrosine Kinase Btk protein, mouse
Topics	Agammaglobulinaemia Tyrosine Kinase Amides (administration & dosage, pharmacokinetics, toxicity) Animals Antineoplastic Agents (administration & dosage, pharmacokinetics, toxicity) Capsules Chromatography, High Pressure Liquid Dogs Excipients Female Gelatin Injections, Intravenous Intestinal Absorption Leukemia (drug therapy) Male Mice Mice, Inbred BALB C Nitriles (administration & dosage, pharmacokinetics, toxicity) Protein-Tyrosine Kinases (antagonists & inhibitors) Rats Rats, Inbred Lew Suspensions Tissue Distribution

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