RESUMO
The triaryl bis-sulfone 1 was modified by converting the aryl A-ring to a piperidine ring. The piperidine ring was further elaborated to a spirocyclopropyl piperidine moiety. The effect on CB2 binding potency, rat calcium channel affinity, and CYP 2C9 inhibition is described.
Assuntos
Receptor CB2 de Canabinoide/antagonistas & inibidores , Sulfonamidas/síntese química , Sulfonas/química , Sulfonas/síntese química , Animais , Canais de Cálcio/metabolismo , Sistema Enzimático do Citocromo P-450 , Agonismo Inverso de Drogas , Humanos , Piperidinas/química , Ratos , Receptor CB2 de Canabinoide/metabolismo , Relação Estrutura-Atividade , Sulfonamidas/química , Sulfonamidas/farmacocinética , Sulfonas/farmacocinéticaRESUMO
Structure-activity relationship on our recently reported triaryl bis-sulfone class of cannabinoid-2 (CB2) receptor selective inverse agonists was explored. Modifications to the methane sulfonamide, substitutions to B and C phenyl rings, and replacements of the C-ring were investigated. A compound with excellent CB2 activity, selectivity for CB2 over CB1, and in vivo plasma levels was identified.
Assuntos
Química Farmacêutica/métodos , Receptor CB2 de Canabinoide/química , Sulfonas/química , Animais , Desenho de Fármacos , Avaliação Pré-Clínica de Medicamentos , Cinética , Ligantes , Modelos Químicos , Ligação Proteica , Ratos , Receptores de Droga , Sódio/química , Relação Estrutura-AtividadeRESUMO
The CC-chemokine receptor 5 (CCR5) is the major coreceptor for macrophage-tropic (R5) HIV-1 strains. Several small molecule inhibitors of CCR5 that block chemokine binding and HIV-1 entry are being evaluated as drug candidates. Here we define how CCR5 antagonists TAK-779, AD101 (SCH-350581) and SCH-C (SCH-351125), which inhibit HIV-1 entry, interact with CCR5. Using a mutagenesis approach in combination with a viral entry assay to provide a direct functional read out, we tested predictions based on a homology model of CCR5 and analyzed the functions of more than 30 amino acid residues. We find that a key set of aromatic and aliphatic residues serves as a hydrophobic core for the ligand binding pocket, while E283 is critical for high affinity interaction, most likely by acting as the counterion for a positively charged nitrogen atom common to all three inhibitors. These results provide a structural basis for understanding how specific antagonists interact with CCR5, and may be useful for the rational design of new, improved CCR5 ligands.
Assuntos
Inibidores da Fusão de HIV/metabolismo , Receptores CCR5/metabolismo , Amidas/metabolismo , Sítios de Ligação/genética , Linhagem Celular , Óxidos N-Cíclicos/metabolismo , HIV-1/crescimento & desenvolvimento , Humanos , Modelos Moleculares , Estrutura Molecular , Mutagênese Sítio-Dirigida , Oximas , Piperidinas/metabolismo , Estrutura Secundária de Proteína , Piridinas/metabolismo , Compostos de Amônio Quaternário/metabolismo , Receptores CCR5/genéticaRESUMO
OBJECTIVE: Collagen-induced arthritis (CIA) in the rhesus monkey is a nonhuman primate model of rheumatoid arthritis (RA). The close phylogenetic relationship between humans and the rhesus monkey makes this model useful for the preclinical safety and efficacy testing of new therapies that are inactive in animals more distinctly related to humans. In this study, we tested the therapeutic potential of a novel, small molecular weight antagonist of CCR5, SCH-X, in this model. METHODS: CIA was induced in 10 rhesus monkeys. The animals were allocated to receive SCH-X or saline as the control (n = 5 in each group). Treatment was initiated on the day of CIA induction and continued for 45 days. Monkeys were monitored before and 63 days after CIA induction for macroscopic signs of clinical arthritis, such as soft-tissue swelling and body weight. Furthermore, markers of inflammation and joint degradation were monitored to follow the disease course. RESULTS: Only 2 of 5 animals in the SCH-X-treated group displayed prominent soft-tissue swelling, compared with all 5 saline-treated monkeys. In addition to the suppression of joint inflammation, treatment with SCH-X resulted in a reduction in joint destruction, as demonstrated by lower rates of urinary excretion of collagen crosslinks, with confirmation by histology. Whereas in all saline-treated monkeys, marked erosion of joint cartilage was observed, this was absent in 4 of the 5 SCH-X-treated monkeys. CONCLUSION: The systemic effects of treatment with SCH-X were a suppressed acute-phase reaction (reduction in C-reactive protein level) in the 3 treated monkeys with CIA that remained asymptomatic, and an altered antibody response toward type II collagen. The results suggest that the CCR5 antagonist SCH-X might have a strong clinical potential for treatment during periods of active inflammation, as seen in RA.
Assuntos
Artrite Experimental/prevenção & controle , Antagonistas dos Receptores CCR5 , Animais , Artrite Experimental/induzido quimicamente , Artrite Experimental/patologia , Cartilagem Articular/patologia , Colágeno Tipo II , Seguimentos , Macaca mulatta , MasculinoRESUMO
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
Anthranilamide analogues such as 23 are potent and highly selective muscarinic M2 antagonists that also show good oral bioavailability and in vivo activity.
Assuntos
Antagonistas Muscarínicos/química , Antagonistas Muscarínicos/farmacologia , Piperidinas/química , Piperidinas/farmacologia , Receptor Muscarínico M2/antagonistas & inibidores , ortoaminobenzoatos/química , Animais , Aprendizagem da Esquiva/efeitos dos fármacos , Bioquímica/métodos , Disponibilidade Biológica , Células CHO , Cricetinae , Relação Dose-Resposta a Droga , Avaliação Pré-Clínica de Medicamentos/métodos , Antagonistas Muscarínicos/farmacocinética , Ratos , Relação Estrutura-AtividadeRESUMO
The unsymmetrical nicotinamide-N-oxide moiety in compound 1 was replaced with symmetrical isonicotinamides as well as 4,6-dimethyl pyrimidine-5-carboxamides. Compound 16 from the latter set reduced the number of rotamers, improved potency of inhibiting UIV entry, slightly diminished the affinity for the muscarine receptors and showed very good oral absorption.
Assuntos
Fármacos Anti-HIV/síntese química , Fármacos Anti-HIV/farmacologia , Antagonistas dos Receptores CCR5 , HIV-1/efeitos dos fármacos , Piperazinas/síntese química , Piperazinas/farmacologia , Administração Oral , Animais , Fármacos Anti-HIV/farmacocinética , Área Sob a Curva , Fenômenos Químicos , Físico-Química , Meia-Vida , Compostos Heterocíclicos/síntese química , Compostos Heterocíclicos/farmacocinética , Compostos Heterocíclicos/farmacologia , Humanos , Injeções Intravenosas , Absorção Intestinal , Conformação Molecular , Piperazinas/farmacocinética , Ratos , Receptores Muscarínicos/efeitos dos fármacos , Relação Estrutura-AtividadeRESUMO
We previously reported the initial discovery of a novel class of stabilized benzylidene ketal M(2) receptor antagonists. This paper discusses new analogues consisting of benzamide modifications which not only improved M(2) receptor affinity and selectivity, but also enhanced the pharmacokinetic properties of the series. These changes led to the discovery of a highly potent and selective M(2) antagonist, which demonstrated in vivo efficacy and had good bioavailability in multiple species.
Assuntos
Benzamidas/química , Compostos de Benzilideno/química , Compostos de Benzilideno/farmacocinética , Antagonistas Muscarínicos/química , Antagonistas Muscarínicos/farmacologia , Receptores Muscarínicos/efeitos dos fármacos , Acetilcolina/análise , Acetilcolina/biossíntese , Animais , Área Sob a Curva , Benzamidas/farmacologia , Desenho de Fármacos , Avaliação Pré-Clínica de Medicamentos , Humanos , Microdiálise , Microssomos Hepáticos/efeitos dos fármacos , Microssomos Hepáticos/metabolismo , Ratos , Receptores Muscarínicos/metabolismo , 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.
RESUMO
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
A novel series of 2-(R)-methyl-substituted piperazines (e.g., 2) is described. They are potent M(2) selective ligands that have >100-fold selectivity versus the M(1) receptor. In the rat microdialysis assay, compound 14 showed significantly enchanced levels of acetylcholine after oral administration.