Reference

Disease-modifying activity of HWA 486 on the development of SLE in MRL/l mice

Disease-modifying activity of HWA 486 on the development of SLE in MRL/l mice. Popovic, S.; Bartlett, R. R. (Dep. Microbiol., Tech. Hochsch. Darmstadt, Darmstadt D-6100, Fed. Rep. Ger.). Agents Actions, 19(5-6), 313-14 (English) 1986. CODEN: AGACBH. ISSN: 0065-4299. DOCUMENT TYPE: Journal CA Section: 1 (Pharmacology) HWA 486 (I) [75706-12-6] prevented proteinuria (glomerulonephritis), splenomegaly, expression of autoantibodies, etc. in autoimmune MRL/1 mice. I also restored the formation of T-cell dependent antibodies to sheep and red blood cell to the levels of normal mice. Thus, I is an immunomodulator with potential for treatment of systemic lupus erythematosus.

Preclinical toxicity and pharmacokinetics of the Bruton's tyrosine kinase-targeting anti-leukemic drug candidate, a-cyano-b-hydroxy-b-methyl-N-(2,5-dibromophenyl) propenamide (LFM-A13)

All Rights Reserved. Preclinical toxicity and pharmacokinetics of the Bruton's tyrosine kinase-targeting anti-leukemic drug candidate, a-cyano-b-hydroxy-b-methyl-N-(2,5-dibromophenyl) propenamide (LFM-A13). Uckun, Fatih M.; Tibbles, Heather; Venkatachalam, Taracad; DuMez, Darin; Erbeck, Douglas (Paradigm Pharmaceuticals, White Bear Lake, MN, USA). Arzneimittel Forschung, 57(1), 31-46 (English) 2007 Editio Cantor Verlag. CODEN: ARZNAD. ISSN: 0004-4172. DOCUMENT TYPE: Journal CA Section: 1 (Pharmacology) The leflunomide (CAS 75706-12-6) metabolite (LFM) analog a-cyano-b-hydroxy-b-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 i.p. bioavailability was estd. 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 vol. of distribution could be attributed to its blood 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 preclin. research studies provide the basis for future pre-IND studies and clin. development of LFM-A13 as an i.v. or orally administered new anti-leukemia agent targeting BTK.