RESUMO
A class of 3,5-diphenyl-1,2,4-oxadiazole based compounds have been identified as potent sphingosine-1-phosphate-1 (S1P1) receptor agonists with minimal affinity for the S1P2 and S1P3 receptor subtypes. Analogue 26 (S1P1 IC50 = 0.6 nM) has an excellent pharmacokinetics profile in the rat and dog and is efficacious in a rat skin transplant model, indicating that S1P3 receptor agonism is not a component of immunosuppressive efficacy.
Assuntos
Imunossupressores/síntese química , Oxidiazóis/síntese química , Receptores de Lisoesfingolipídeo/agonistas , Animais , Células CHO , Cricetinae , Cricetulus , Cães , Sobrevivência de Enxerto , Imunossupressores/farmacocinética , Imunossupressores/farmacologia , Contagem de Linfócitos , Oxidiazóis/farmacocinética , Oxidiazóis/farmacologia , Ensaio Radioligante , Ratos , Ratos Endogâmicos Lew , Ratos Sprague-Dawley , Transplante de Pele , Relação Estrutura-AtividadeRESUMO
Moderately potent, selective S1P(1) receptor agonists identified from high-throughput screening have been adapted into lipophilic tails for a class of orally bioavailable amino acid-based S1P(1) agonists represented by 7. Many of the new compounds are potent S1P(1) agonists that select against the S1P(2), S1P(3), and S1P(4) (although not S1P(5)) receptor subtypes. Analogues 18 and 24 are highly orally bioavailable and possess excellent pharmacokinetic profiles in the rat, dog, and rhesus monkey.
Assuntos
Azetidinas/farmacologia , Imunossupressores/farmacologia , Receptores de Lisoesfingolipídeo/agonistas , Administração Oral , Animais , Azetidinas/farmacocinética , Disponibilidade Biológica , Células CHO , Cricetinae , Cães , Desenho de Fármacos , Guanosina 5'-O-(3-Tiotrifosfato)/metabolismo , Humanos , Imunossupressores/farmacocinética , Linfócitos/efeitos dos fármacos , Macaca mulatta , Camundongos , Ratos , Ratos Endogâmicos Lew , Relação Estrutura-AtividadeRESUMO
[reaction: see text] A novel approach to alpha,alpha-disubstituted-beta-amino acids (beta(2,2)-amino acids) was employed in the synthesis of a series of 3-(pyrrolidin-1-yl)propionic acids possessing high affinity for the CCR5 receptor and potent anti-HIV activity. The rat pharmacokinetics for these new analogues featured higher bioavailabilities and lower rates of clearance as compared to cyclopentane 1.
Assuntos
Fármacos Anti-HIV/farmacologia , Antagonistas dos Receptores CCR5 , Propionatos/farmacologia , Pirrolidinas/farmacologia , Fármacos Anti-HIV/farmacocinética , Disponibilidade Biológica , Propionatos/farmacocinética , Pirrolidinas/farmacocinéticaRESUMO
The molecular chaperone HSP90 has been shown to facilitate cancer cell survival by stabilizing key proteins responsible for a malignant phenotype. We report here the results of parallel fragment-based drug design approaches in the design of novel HSP90 inhibitors. Initial aminopyrimidine leads were elaborated using high-throughput organic synthesis to yield nanomolar inhibitors of the enzyme. Second site leads were also identified which bound to HSP90 in two distinct conformations, an 'open' and 'closed' form. Intriguingly, linked fragment approaches targeting both of these conformations were successful in producing novel, micromolar inhibitors. Overall, this study shows that, with only a few fragment hits, multiple lead series can be generated for HSP90 due to the inherent flexibility of the active site. Thus, ample opportunities exist to use these lead series in the development of clinically useful HSP90 inhibitors for the treatment of cancers.
Assuntos
Desenho de Fármacos , Inibidores Enzimáticos , Proteínas de Choque Térmico HSP90/antagonistas & inibidores , Fragmentos de Peptídeos , Aminopiridinas/química , Aminopiridinas/metabolismo , Cristalografia por Raios X , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Inibidores Enzimáticos/metabolismo , Humanos , Ligantes , Modelos Moleculares , Dados de Sequência Molecular , Estrutura Molecular , Ressonância Magnética Nuclear Biomolecular , Fragmentos de Peptídeos/química , Fragmentos de Peptídeos/metabolismo , Conformação ProteicaRESUMO
A series of 2-aryl(pyrrolidin-4-yl)acetic acids were synthesized and their biological activities were evaluated as agonists of S1P receptors. These analogs were able to induce lowering of lymphocyte counts in the peripheral blood of mice and were found to have good overall pharmacokinetic properties in rat.
Assuntos
Acetatos/farmacologia , Pirrolidinas/farmacologia , Receptores de Lisoesfingolipídeo/agonistas , Acetatos/síntese química , Acetatos/química , Animais , Contagem de Linfócitos , Lisofosfolipídeos/antagonistas & inibidores , Camundongos , Estrutura Molecular , Ligação Proteica/efeitos dos fármacos , Pirrolidinas/síntese química , Pirrolidinas/química , Ratos , Esfingosina/análogos & derivados , Esfingosina/antagonistas & inibidores , Estereoisomerismo , Relação Estrutura-AtividadeRESUMO
A series of 1,3,4-trisubstituted pyrrolidine CCR5 receptor antagonists containing a variety of fused heterocycles at the 4-position of the piperidine side chain has been discovered, which are orally bioavailable with potent anti-HIV activity.
Assuntos
Fármacos Anti-HIV/química , Antagonistas dos Receptores CCR5 , Compostos Heterocíclicos/química , Pirrolidinas/química , Administração Oral , Animais , Fármacos Anti-HIV/farmacocinética , Células HeLa , Compostos Heterocíclicos/farmacocinética , Humanos , Pirrolidinas/farmacocinética , Ratos , Receptores CCR5/metabolismoRESUMO
Blood lymphocyte numbers, essential for the development of efficient immune responses, are maintained by recirculation through secondary lymphoid organs. We show that lymphocyte trafficking is altered by the lysophospholipid sphingosine-1-phosphate (S1P) and by a phosphoryl metabolite of the immunosuppressive agent FTY720. Both species were high-affinity agonists of at least four of the five S1P receptors. These agonists produce lymphopenia in blood and thoracic duct lymph by sequestration of lymphocytes in lymph nodes, but not spleen. S1P receptor agonists induced emptying of lymphoid sinuses by retention of lymphocytes on the abluminal side of sinus-lining endothelium and inhibition of egress into lymph. Inhibition of lymphocyte recirculation by activation of S1P receptors may result in therapeutically useful immunosuppression.
Assuntos
Linfócitos B/fisiologia , Lisofosfolipídeos , Organofosfatos/farmacologia , Organofosfonatos/farmacologia , Propilenoglicóis/metabolismo , Receptores de Superfície Celular/agonistas , Receptores Acoplados a Proteínas G , Esfingosina/análogos & derivados , Esfingosina/farmacologia , Linfócitos T/fisiologia , Animais , Linfócitos B/efeitos dos fármacos , Ligação Competitiva , Células CHO , Cálcio/metabolismo , Cricetinae , AMP Cíclico/metabolismo , Cloridrato de Fingolimode , Guanosina 5'-O-(3-Tiotrifosfato)/metabolismo , Humanos , Imunossupressores/metabolismo , Imunossupressores/farmacologia , Ligantes , Linfonodos/citologia , Linfonodos/efeitos dos fármacos , Contagem de Linfócitos , Linfopenia/induzido quimicamente , Camundongos , Organofosfatos/síntese química , Organofosfatos/química , Organofosfatos/metabolismo , Organofosfonatos/síntese química , Organofosfonatos/química , Organofosfonatos/metabolismo , Fosforilação , Propilenoglicóis/farmacologia , Ratos , Receptores de Superfície Celular/metabolismo , Receptores de Lisofosfolipídeos , Esfingosina/metabolismo , Baço/citologia , Baço/efeitos dos fármacos , Estereoisomerismo , Linfócitos T/efeitos dos fármacosRESUMO
The results of investigations in these laboratories of 2-aryl-4-(piperidin-1-yl)butanamines and 1,3,4-trisubstituted pyrrolidines as human CCR5 antagonists have recently been disclosed. To facilitate further development of these antagonists, we have developed a pharmacophore model based on the structure-activity relationships (SAR) and a human CCR5 receptor docking model using the crystal structure of rhodopsin as a template [Palczewski, K., et al. (2000) Science 289, 739-745]. Guided by the receptor docking model, we have mapped the compounds' site of interaction with CCR5 using site-directed mutagenesis experiments. Our results are consistent with a binding site for the two series that is located within a cavity near the extracellular surface formed by transmembrane helices 2, 3, 6, and 7. This site is overlapping yet distinct from that reported for another antiviral agent which binds to CCR5 [Dragic, T., et al. (2000) Proc. Natl. Acad. Sci. U.S.A. 97, 5639-5644].
Assuntos
Butanos/química , Antagonistas dos Receptores CCR5 , Modelos Moleculares , Mutagênese Sítio-Dirigida , Piperidinas/química , Pirrolidinas/química , Receptores CCR5/química , Alanina/genética , Amidas/química , Sequência de Aminoácidos , Substituição de Aminoácidos/genética , Animais , Sítios de Ligação/genética , Ligação Competitiva/genética , Células CHO , Bovinos , Cricetinae , Humanos , Dados de Sequência Molecular , Estrutura Secundária de Proteína/genética , Compostos de Amônio Quaternário/química , Receptores CCR5/biossíntese , Receptores CCR5/genética , Rodopsina/química , Homologia de Sequência de Aminoácidos , Relação Estrutura-AtividadeRESUMO
A series of conformationally constrained 3-(N-alkylamino)propylphosphonic acids were systematically synthesized and their activities as S1P receptor agonists were evaluated. Several pyrrolidine and cyclohexane analogs had S1P receptor profiles comparable to the acyclic lead compound, 3-(N-tetradecylamino)propylphosphonic acid (3), lowered circulating lymphocytes in mice after iv administration and were thus identified as being suitable for further investigations.
Assuntos
Desenho de Fármacos , Organofosfonatos/síntese química , Receptores de Lisoesfingolipídeo/agonistas , Animais , Células CHO , Cricetinae , Humanos , Conformação Molecular , Organofosfonatos/química , Organofosfonatos/farmacologia , Relação Estrutura-AtividadeRESUMO
A series of CCR5 antagonists containing bicyclic isoxazolidines was generated through a nitrone mediated cycloaddition with olefins bearing the preferred pharmacophores previously described. Potent antagonists (3 and 16) were generated with enhanced affinity for the CCR5 receptor while maintaining antiviral activity against HIV.
Assuntos
Fármacos Anti-HIV/síntese química , Antagonistas dos Receptores CCR5 , Isoxazóis/síntese química , Fármacos Anti-HIV/farmacologia , Compostos Bicíclicos Heterocíclicos com Pontes/síntese química , Compostos Bicíclicos Heterocíclicos com Pontes/química , Compostos Bicíclicos Heterocíclicos com Pontes/farmacologia , HIV-1/efeitos dos fármacos , Humanos , Isoxazóis/química , Isoxazóis/farmacologia , Testes de Sensibilidade Microbiana , Conformação Molecular , Ligação Proteica , Pirrolidinas/síntese química , Pirrolidinas/química , Pirrolidinas/farmacologia , Relação Estrutura-AtividadeRESUMO
Modifications of the alkyl acetic acid portion and the phenyl on pyrrolidine in our lead pyrazole compound 1 afforded the isopropyl compound 9. This compound is a potent CCR5 antagonist showing good in vitro antiviral activity against HIV-1, an excellent selectivity profile, and good oral bioavailability in three animal species. During this investigation, a new method for the preparation of alpha-(pyrrolidin-1-yl)-alpha,alpha-dialkyl acetic acid from a pyrrolidine and alpha-bromo-alpha,alpha-dialkyl acetic acid using silver triflate was discovered. This allowed us to prepare compounds such as 24 and 25 for the first time. A novel Pd-mediated N-dealkylation of alpha-(pyrrolidin-1-yl)acetic acid was also uncovered.
Assuntos
Fármacos Anti-HIV/síntese química , Fármacos Anti-HIV/farmacocinética , Antagonistas dos Receptores CCR5 , Piperidinas/síntese química , Piperidinas/farmacocinética , Acetatos/química , Acetatos/farmacocinética , Administração Oral , Animais , Fármacos Anti-HIV/química , Disponibilidade Biológica , Cães , Células HeLa , Humanos , Macaca mulatta , Estrutura Molecular , Monócitos/efeitos dos fármacos , Piperidinas/química , Pirazóis/química , Pirazóis/farmacocinética , Ratos , Relação Estrutura-AtividadeRESUMO
A series of alpha-(pyrrolidin-1-yl)acetic acids is presented as selective and potent antivirals against HIV. Several of the pyrrolidine zwitterions demonstrated reasonable in vitro properties, enhanced antiviral activities and improved pharmacokinetic profiles over pyrrolidine 1.
Assuntos
Fármacos Anti-HIV/síntese química , Fármacos Anti-HIV/farmacologia , Antagonistas dos Receptores CCR5 , HIV-1/efeitos dos fármacos , Pirrolidinas/síntese química , Pirrolidinas/farmacologia , Animais , Fármacos Anti-HIV/farmacocinética , Células CHO , Permeabilidade da Membrana Celular , Fenômenos Químicos , Físico-Química , Quimiocina CCL4 , Cricetinae , Células HeLa , Humanos , Indicadores e Reagentes , Proteínas Inflamatórias de Macrófagos/antagonistas & inibidores , Pirrolidinas/farmacocinética , Ratos , Relação Estrutura-AtividadeRESUMO
The 4-(3-phenylprop-1-yl)piperidine moiety of the 1,3,4-trisubstituted pyrrolidine CCR5 antagonist 1 was modified with electron deficient aromatics as well as replacement of the benzylic methylene with sulfones, gem-difluoromethylenes and alcohols in an effort to balance the antiviral potency with reasonable pharmacokinetics.