Mark S. Bednarz

A new facile method for the synthesis of 1-arylimidazole-5-carboxylates

Abstract A new facile method for the preparation of 1-arylimidazole-5-carboxylates was developed. The new method involved reaction of anilines and ethyl glyoxylate in methanol to give α-anilino-α-methoxyacetates followed by cyclization with TosMIC, affording 1-arylimidazole-5-carboxylates in two steps in 40–94% overall yields.

Inhibition of Sphingosine 1-Phosphate Lyase for the Treatment of Rheumatoid Arthritis: Discovery of (E)-1-(4-((1R,2S,3R)-1,2,3,4-Tetrahydroxybutyl)-1H-imidazol-2-yl)ethanone Oxime (LX2931) and (1R,2S,3R)-1-(2-(Isoxazol-3-yl)-1H-imidazol-4-yl)butane-1,2,3,4-tetraol (LX2932)

Sphingosine 1-phosphate lyase (S1PL) has been characterized as a novel target for the treatment of autoimmune disorders using genetic and pharmacological methods. Medicinal chemistry efforts targeting S1PL by direct in vivo evaluation of synthetic analogues of 2-acetyl-4(5)-(1(R),2(S),3(R),4-tetrahydroxybutyl)-imidazole (THI, 1) led to the discovery of 2 (LX2931) and 4 (LX2932). The immunological phenotypes observed in S1PL deficient mice were recapitulated by oral administration of 2 or 4. Oral dosing of 2 or 4 yielded a dose-dependent decrease in circulating lymphocyte numbers in multiple species and showed a therapeutic effect in rodent models of rheumatoid arthritis (RA). Phase I clinical trials indicated that 2, the first clinically studied inhibitor of S1PL, produced a dose-dependent and reversible reduction of circulating lymphocytes and was well tolerated at dose levels of up to 180 mg daily. Phase II evaluation of 2 in patients with active rheumatoid arthritis is currently underway.

Novel triethylsilane mediated reductive N-alkylation of amines: improved synthesis of 1-(4-imidazolyl)methyl-4-sulfonylbenzodiazepines, new farnesyltransferase inhibitors

An improved synthesis of 1-(imidazolyl)methyl-4-sulfonylbenzodiazapines, new farnesyltransferase inhibitors, was achieved using a novel reductive N-alkylation method. The new method involves reaction of a secondary amine with an aldehyde using triethylsilane in the presence of trifluoroacetic acid, giving a tertiary amine in 90–95% isolated yields.

Rapid synthesis of triazine inhibitors of inosine monophosphate dehydrogenase

A series of novel triazine-based small molecule inhibitors (IV) of inosine monophosphate dehydrogenase was prepared. The synthesis and the structure-activity relationships (SAR) derived from in vitro studies are described.

Reaction of quinoxalin-2-ones with TosMIC reagent: synthesis of imidazo[1,5-a]quinoxalin-4-ones

Abstract Imidazo[1,5-a]quinoxalin-4-ones were prepared in four steps starting from 1,2-phenylenediamines using a new strategy for the construction of the ring system. A key step in this new method involves the reaction of quinoxalin-2-ones with TosMIC (tosylmethyl isocyanide).

BMS-196085: A potent and selective full agonist of the human β3 adrenergic receptor

A series of 4-hydroxy-3-methylsulfonanilido-1,2-diarylethylamines were prepared and evaluated for their human beta(3) adrenergic receptor agonist activity. SAR studies led to the identification of BMS-196085 (25), a potent beta(3) full agonist (K(i)=21 nM, 95% activation) with partial agonist (45%) activity at the beta(1) receptor. Based on its desirable in vitro and in vivo properties, BMS-196085 was chosen for clinical evaluation.

Synthesis of deuterium-labeled atorvastatin and its metabolites for use as internal standards in a LC/MS/MS method developed for quantitation of the drug and its metabolites in human serum

D5-labeled isotopomers of atorvastatin, atorvastatin lactone and its hydroxy metabolites were synthesized as internal standards for use in a LC/MS/MS method developed for the simultaneous quantitative determination of atorvastatin and its hydroxy metabolites in human serum. d5-Atorvastatin and d5-atorvastatin lactone were prepared from d5-aniline whereas their corresponding hydroxy metabolites were synthesized using d5-benzaldehyde. Copyright

A new highly enantioselective synthesis of both (R)- and (S)-2-mercaptosuccinic acids

Abstract (R)- and (S)-2-Mercaptosuccinic acids 4 were prepared in five steps in >96% ee and 49–52% overall yield via a new efficient synthesis starting from commercially available L- and D-aspartic acids.

Design and Synthesis of a G-Protein-Coupled Receptor Antagonist Library of Aryloxyalkanolamines Using a Polymer-Supported Acyclic Acetal Linker

A G-Protein-coupled receptor-targeted library of aryloxypropanolamines and aryloxybutanolamines was efficiently executed using a novel, polymer-supported acyclic acetal linker, producing compounds in good yields and purities.