RESUMO
Inhibition of stearoyl-CoA desaturase (SCD) activity represents a potential novel mechanism for the treatment of metabolic disorders including obesity and type II diabetes. To circumvent skin and eye adverse events observed in rodents with systemically-distributed SCD inhibitors, our research efforts have been focused on the search for new and structurally diverse liver-targeted SCD inhibitors. This work has led to the discovery of novel, potent and structurally diverse liver-targeted bispyrrolidine SCD inhibitors. These compounds possess suitable cellular activity and pharmacokinetic properties to inhibit liver SCD activity in a mouse pharmacodynamic model.
Assuntos
Inibidores Enzimáticos/farmacologia , Fígado/efeitos dos fármacos , Pirrolidinas/farmacologia , Estearoil-CoA Dessaturase/antagonistas & inibidores , Animais , Relação Dose-Resposta a Droga , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Células Hep G2 , Humanos , Fígado/enzimologia , Fígado/metabolismo , Estrutura Molecular , Pirrolidinas/síntese química , Pirrolidinas/química , Ratos , Estearoil-CoA Dessaturase/metabolismo , Estereoisomerismo , Relação Estrutura-AtividadeRESUMO
Practical, chromatography-free syntheses of 5-lipoxygenase inhibitor MK-0633 p-toluenesulfonate (1) are described. The first route used an asymmetric zincate addition to ethyl 2,2,2-trifluoropyruvate followed by 1,3,4-oxadiazole formation and reductive amination as key steps. An improved second route features an inexpensive diastereomeric salt resolution of vinyl hydroxy-acid 22 followed by a robust end-game featuring a through-process hydrazide acylation/1,3,4-oxadiazole ring closure/salt formation sequence to afford MK-0633 p-toluenesulfonate (1).
Assuntos
Benzenossulfonatos/síntese química , Benzopiranos/síntese química , Inibidores de Lipoxigenase , Inibidores de Lipoxigenase/síntese química , Oxidiazóis/síntese química , Araquidonato 5-Lipoxigenase/química , Benzenossulfonatos/química , Benzopiranos/química , Inibidores de Lipoxigenase/química , Estrutura Molecular , Oxidiazóis/química , EstereoisomerismoRESUMO
An enantioselective synthesis of the Cathepsin K inhibitor odanacatib (MK-0822) 1 is described. The key step involves the novel stereospecific S(N)2 triflate displacement of a chiral alpha-trifluoromethylbenzyl triflate 9a with (S)-gamma-fluoroleucine ethyl ester 3 to generate the required alpha-trifluoromethylbenzyl amino stereocenter. The triflate displacement is achieved in high yield (95%) and minimal loss of stereochemistry. The overall synthesis of 1 is completed in 6 steps in 61% overall yield.
Assuntos
Compostos de Bifenilo/síntese química , Catepsinas/antagonistas & inibidores , Hidrocarbonetos Fluorados/química , Inibidores de Proteases/síntese química , Álcoois/química , Compostos de Bifenilo/química , Catepsina K , Ésteres/química , Hidrólise , Inibidores de Proteases/química , Estereoisomerismo , Especificidade por SubstratoRESUMO
A practical, kilogram-scale chromatography-free synthesis of mPGE synthase I inhibitor MK-7285 is described. The route features a convergent assembly of the core phenanthrene unit via amide-directed ortho-metalation and proximity-induced anionic cyclization, followed by imidazole synthesis and late-stage cyanation.
Assuntos
Inibidores Enzimáticos/química , Inibidores Enzimáticos/síntese química , Compostos Heterocíclicos de 4 ou mais Anéis/química , Compostos Heterocíclicos de 4 ou mais Anéis/síntese química , Oxirredutases Intramoleculares/química , Ciclização , Estrutura Molecular , Prostaglandina-E SintasesRESUMO
A practical and efficient synthesis of bradykinin B(1) antagonist 1 is described. A convergent strategy was utilized which involved synthesis of three fragments: 3, 6, and 7. Cross coupling of fragments 6 and 7 followed by amidation with 3 enabled efficient synthesis of 1 in 19 steps total, a 35% overall yield from commercially available pyridine 10. The key to the success of the synthesis was the development of a fluorodenitration step to install the fluorine in pyridine 7 and a catalytic enantioselective hydrogenation of N-acyl enamide 9 to set the stereochemistry.
Assuntos
Amidas/síntese química , Antagonistas de Receptor B1 da Bradicinina , Piridinas/síntese química , Amidas/química , Amidas/farmacologia , Aminas/síntese química , Aminas/química , Azóis/síntese química , Azóis/química , Ácidos Borônicos/síntese química , Ácidos Borônicos/química , Hidrocarbonetos Fluorados/síntese química , Hidrocarbonetos Fluorados/química , Hidrogenação , Metilação , Piridinas/química , Piridinas/farmacologia , EstereoisomerismoRESUMO
A novel HIV protease inhibitor was designed using a morpholine core as the aspartate binding group. Analysis of the crystal structure of the initial lead bound to HIV protease enabled optimization of enzyme potency and antiviral activity. This afforded a series of potent orally bioavailable inhibitors of which MK-8718 was identified as a compound with a favorable overall profile.
RESUMO
Two chiral cyclohexanones were linked to polystyrene resin. The polymer-bound auxiliaries were subjected to a sequence of four reactions, the last of which cleaves the desired alpha-chiral carbonyl compound off the resin, concurrently regenerating the resin-bound auxiliary in its original form. The resin can then be reused.