RESUMO
The nature and the size of the benzylic substituent are shown to be the key to controlling receptor selectivity (CCR5 vs M1, M2) and potency in the title compounds. Optimization of the lead benzylic methyl compound 3 led to the methoxymethyl analogue 30, which had excellent receptor selectivity and oral bioavailability in rats and monkeys. Compound 30 (Sch-417690/Sch-D), a potent inhibitor of HIV-1 entry into target cells, is currently in clinical trials.
Assuntos
Fármacos Anti-HIV/síntese química , Antagonistas dos Receptores CCR5 , HIV-1/efeitos dos fármacos , Piperazinas/síntese química , Piperidinas/síntese química , Canais de Potássio de Abertura Dependente da Tensão da Membrana , Pirimidinas/síntese química , Administração Oral , Animais , Fármacos Anti-HIV/efeitos adversos , Fármacos Anti-HIV/farmacologia , Disponibilidade Biológica , Encéfalo/efeitos dos fármacos , Proteínas de Transporte de Cátions/efeitos dos fármacos , Sistema Digestório/efeitos dos fármacos , Canais de Potássio Éter-A-Go-Go , HIV-1/isolamento & purificação , Humanos , Técnicas In Vitro , Leucócitos Mononucleares/efeitos dos fármacos , Leucócitos Mononucleares/virologia , Macaca fascicularis , Piperazinas/efeitos adversos , Piperazinas/química , Piperazinas/farmacologia , Piperidinas/química , Piperidinas/farmacologia , Canais de Potássio/efeitos dos fármacos , Pirimidinas/efeitos adversos , Pirimidinas/química , Pirimidinas/farmacologia , Ratos , Estereoisomerismo , Relação Estrutura-AtividadeRESUMO
The synthesis and muscarinic binding properties of compounds based on the 1-[4-(4-arylsulfonyl)phenylmethyl]-4-(1-aroyl-4-piperidinyl)-piperazine skeleton are described. For compounds, substituted with appropriately configured methyl groups at the benzylic center and at the piperazine 2-position, high levels of selective, M(2) subtype affinity could be obtained, particularly when the terminal N-aroyl residue was ortho-substituted.
Assuntos
Piperazinas/síntese química , Piperazinas/metabolismo , Receptores Muscarínicos/metabolismo , Sítios de Ligação , Ligantes , Estrutura Molecular , Piperazinas/química , Receptor Muscarínico M1 , Receptor Muscarínico M2 , Relação Estrutura-AtividadeRESUMO
Aryl carboxamides are useful structural units found in several biologically active compounds. Unlike their benzoic acid counterparts, fluorinated versions of naphthoic acids are relatively unknown. In connection with a recent project, we needed viable syntheses of several mono- and difluorinated naphthoic acids. Herein we describe the synthesis of 5-, 6-, 7-, and 8-fluoro-1-naphthalenecarboxylic acids and 5,7-, 5,8-, 6,7-, and 4,5-difluoro-1-naphthalenecarboxylic acids. The 5-fluoro derivative 1was obtained from the corresponding 5-bromo compound via electrophilic fluorination of the lithio-intermediate. The rest of the monofluoro (2, 3, and 4) and the difluoro acids (5, 6, and 7) were prepared by a new, general route which entailed the elaboration of commercial fluorinated phenylacetic acids to 2-(fluoroaryl)glutaric acids with differential ester groups; selective hydrolysis to a mono acid, intramolecular Friedel-Crafts cyclization, and aromatization furnished the target structures. An alternative process to assemble a naphthalene skeleton is also presented for the difluoro acids 5 and 6. Finally, 4,5-difluoro-1-naphthalenecarboxylic acid (8) was prepared expeditiously from 1,8-diaminonaphthalene by adapting classical reactions.