Large-scale synthesis of GMP grade N'- [2-(2-thiophene) ethyl]-N'- [2- (5-bromopyridyl)] -thiourea (HI-443), a new anti-HIV drug candidate.

The thiourea compound N'-[2-(2-thiophene)ethyl]-N'-[2-(5-bromopyridyl)]-thiourea (HI-443, CAS 258340-15-7), was found to be a potent anti-HIV agent with remarkable activity against nucleoside analog reverse transcriptase (NRT)-resistant, non-nucleoside analog reverse transcriptase (NNRT)-resistant, as well as multidrug-resistant HIV. Now the method of producing HI-443 under current Good Manufacturing Practice (cGMP) conditions on the scale of kilograms is reported. The availability of GMP-grade HI-443 will promote the preclinical and clinical development efforts aimed at making this new drug candidate available to HIV-infected persons.

Large-scale synthesis of GMP grade alpha-cyano-beta-hydroxy-beta-methyl-N-(2,5-dibromophenyl) propenamide (LFM-A13), a new anti-cancer drug candidate.

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 inhibitor of the anti-apoptotic enzyme Bruton's tyrosine kinase (BTK). LFM-A13 is being developed as a novel dual-function anticancer drug with apoptosis-promoting and anti-thrombotic properties. LFM-A13 was prepared under current Good Manufacturing Practice (cGMP) conditions on the scale of kilograms.

Anti-retroviral activity of GMP-grade stampidine against genotypically and phenotypically nucleoside reverse transcriptase inhibitor resistant recombinant human immunodeficiency virus. An in vitro study.

The in vitro potency of GMP-grade stampidine (CAS 217178-62-6) was examined against 3 clinical HIV-1 isolates and 6 recombinant HIV-1 clones with multi-NRTI 'resistance (NRTI: nucleoside reverse transcriptase inhibitors). GMP-grade stampidine active drug substance (Lot #'s MPR-M0008.00-01 and MPR-M0008.

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%.

Large-scale synthesis and formulation of GMP-grade stampidine, a new anti-HIV agent.

The arylphosphoramidate derivative of stavudine (STV, d4T, 2,3'-didehydro-3'-deoxythymidine, CAS 3056-17-5), stampidine (STAMP, DDE-113, HI-113, N-[p-(4-bromophenyl)-2',3'-didehydro-3'-deoxy-5'-thymidylyl]-L-alanine methyl ester, CAS 217178-62-6), is a novel anti-HIV agent. STAMP was prepared under current Good Manufacturing Practice (cGMP) conditions on the scale of kilograms. Solid STAMP was subsequently formulated as a capsule under GMP conditions for oral administration.

Targeting JAK3 and BTK tyrosine kinases with rationally-designed inhibitors.

Multifunctional rational drug design of protein tyrosine kinases inhibitors allows a potent drug to be utilized to treat more than one disease for greater patient benefits. Many protein tyrosine kinases (PTK), including Janus kinase 3 (JAK3) and Bruton's tyrosine kinase (BTK), have been identified as potential drug targets to treat diverse diseases including cancer and disorders of the immune system. Here we review advances in JAK3 and BTK inhibitors and describe the therapeutic potential of these potent agents in the clinical setting.

Synthesis and Structure of Bis(pi-cyclopentadienyl)vanadium(IV) 1,10-Phenanthroline and 2,2'-Bipyridine Compounds and Their Interactions with Artificial Membranes.

The reaction of in situ generated Cp(2)V(OTf)(2) (Cp = cyclopentadienyl; OTf = O(3)SCF(3)) with excess 1,10-phenanthroline and 2,2'-bipyridine yields the d(1) vanadocene coordination compounds [Cp(2)V(phen)][OTf](2) (1) and [Cp(2)V(bpy)][OTf](2) (2), respectively. The compounds have been characterized by UV-vis and EPR spectroscopy and by cyclic voltammetry. The complexes have relatively low vanadium(IV)-vanadium(III) reduction potentials (-0.

Fluoride Reactions with Hydrotris(pyrazolyl)borate Rhenium Oxo Complexes: Re-F vs B-F Bond Formation.

Rhenium-oxo-fluoride complexes are readily prepared using hydrotris(3,5-dimethyl-1-pyrazolyl)borate [HB(3,5-Me(2)pz)(3)(-), Tp] as a supporting ligand. For instance, treatment of TpRe(O)(OH)Cl with concentrated aqueous HF cleanly forms the chloro-fluoride complex TpRe(O)(F)Cl. Related fluoro-iodide, fluoro-triflate, and difluoride complexes are also described.

Synthesis and Characterization of Rhenium(VI) cis-Dioxo Complexes and Examination of Their Redox Chemistry.

Reaction of rhenium(V)-oxo-halo-triflate complexes (HB(pz)(3))ReO(X)OTf (1, X = Cl, Br, I) with 1 equiv of pyridine N-oxide forms rare d(1) rhenium(VI) cis-dioxo compounds (HB(pz)(3))ReO(2)X (2, X = Cl, Br, I). This reaction likely occurs by initial formation of the d(0) rhenium(VII) dioxo cation (HB(pz)(3))ReO(2)X(+) by oxygen atom transfer, followed by a rapid one electron reduction. The chloride derivative 2a has been characterized by an X-ray crystal structure.