Arzneimittelforschung 2007; 57(1): 31-46
DOI: 10.1055/s-0031-1296583
Antibiotics · Antiviral Drugs · Chemotherapeutics · Cytostatics
Editio Cantor Verlag Aulendorf (Germany)

Preclinical Toxicity and Pharmacokinetics of the Bruton's Tyrosine Kinase-Targeting Anti-leukemic Drug Candidate, α-Cyano-β-Hydroxy-β-Methyl-N-(2,5-Dibromophenyl) Propenamide (LFM-A13)

Fatih M. Uckun
1  Paradigm Pharmaceuticals, White Bear Lake, MN, USA
2  Parker Hughes Cancer Center, St. Paul, MN, USA
,
Heather Tibbies
1  Paradigm Pharmaceuticals, White Bear Lake, MN, USA
,
Taracad Venkatachalam
1  Paradigm Pharmaceuticals, White Bear Lake, MN, USA
,
Darin DuMez
1  Paradigm Pharmaceuticals, White Bear Lake, MN, USA
,
Douglas Erbeck
2  Parker Hughes Cancer Center, St. Paul, MN, USA
› Author Affiliations
Further Information

Publication History

Publication Date:
21 December 2011 (online)

Abstract

Theleflunomide (CAS 75706-12-6) metabolite (LFM) analog α-cyano-β-hydroxy-β-methyl-N-(2,5-dibromophenyl)-propena-mide (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-I 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 clinical development of LFM-A13 as an intravenously or orally administered new anti-leukemia agent targeting BTK.