RESUMO
The results of a statistical analysis of more than 84,000 compounds from lead optimization programs against 30 different protein targets is presented, with a focus on the effects that different chemical substituents have on compound potency. It is observed that the potency changes induced by most chemical groups follows a nearly normal distribution centered near zero (i.e., no effect on potency). However, the widths of the distributions vary significantly between different substituents, and these effects cannot be rationalized by simple physicochemical parameters. In addition, certain substituents consistently bias the distribution toward higher or lower potency, suggesting the existence of preferred and nonpreferred chemical groups for lead optimization. The implications of these results for understanding protein-ligand recognition and for enhancing the efficiency and speed of lead optimization will be discussed.
Assuntos
Preparações Farmacêuticas/química , Proteínas/química , Artefatos , Fenômenos Químicos , Físico-Química , Interpretação Estatística de Dados , Ligantes , Modelos Moleculares , Estrutura Molecular , Relação Estrutura-AtividadeRESUMO
This manuscript details the construction of a fully automated flow hydrogenation apparatus for use in high-throughput organic synthesis. The instrument comprises of a Bohdan robot platform coupled with a ThalesNano H-cube hydrogenator and a series of solvent valves and pumping mechanisms. Using this instrument, we have been able to fully automate a number of key transformations that could not otherwise be conveniently undertaken in a high-throughput manner.
Assuntos
Química Orgânica/instrumentação , Técnicas de Química Combinatória/instrumentação , Desenho de Fármacos , Robótica , Catálise , Química Orgânica/métodos , Técnicas de Química Combinatória/métodos , Desenho de Equipamento , Hidrogenação , Reprodutibilidade dos Testes , Bibliotecas de Moléculas Pequenas/químicaRESUMO
All reported GnRH receptor mutants (causing human hypogonadotropic hypogonadism) are misfolded proteins that cannot traffic to the plasma membrane. Pharmacoperones correct misfolding and rescue mutants, routing them to the plasma membrane where they regain function. Because pharmacoperones are often peptidomimetic antagonists, these must be removed for receptor function after rescue; in vivo this necessitates pulsatile pharmacoperone administration. As an antecedent to in vivo studies, we determined whether pharmacoperones need to be present at the time of synthesis or whether previously misfolded proteins could be refolded and rescued. Accordingly, we blocked either protein synthesis or intra-cellular transport. Biochemical and morphological studies using 12 mutants and 10 pharmacoperones representing three different chemical classes show that previously synthesized mutant proteins, retained by the quality control system (QCS), are rescued by pharmacoperones, showing that pharmacoperone administration in vivo likely need not consider whether the target protein is being synthesized at the time of drug administration.
Assuntos
Chaperonas Moleculares/farmacologia , Dobramento de Proteína , Processamento de Proteína Pós-Traducional/efeitos dos fármacos , Receptores Acoplados a Proteínas G/metabolismo , Receptores LHRH/metabolismo , Animais , Compostos Bicíclicos Heterocíclicos com Pontes/farmacologia , Células COS , Chlorocebus aethiops , Avaliação Pré-Clínica de Medicamentos , Células HeLa , Humanos , Indóis/farmacologia , Inositol/farmacologia , Mimetismo Molecular , Proteínas Mutantes/química , Proteínas Mutantes/genética , Proteínas Mutantes/metabolismo , Transporte Proteico/efeitos dos fármacos , Piridinas/farmacologia , Receptores Acoplados a Proteínas G/química , Receptores Acoplados a Proteínas G/genética , Receptores LHRH/química , Receptores LHRH/genética , TransfecçãoRESUMO
In our efforts to further pursue one of the most selective dopamine D(3)-receptor antagonists reported to date, we now describe the synthesis and SAR of novel and highly selective dopamine D(3) antagonists based on a 1H-pyridin-2-one or on a urea scaffold. The most potent compounds exhibited K(i) values toward the D(3) receptor in the nano- to subnanomolar range and high selectivity versus the related D(2) dopamine receptor. Thus, 1H-pyridin-2-one 7b displays oral bioavailability (F=37%) as well as brain penetration (brain plasma ratio 3.7) in rat. Within the urea series, an excellent D(3) versus D(2) selectivity (>100-fold) could be achieved by removal of one NH group (compound 6), although bioavailability (rat) was suboptimal (F<10%). These data significantly enhance our understanding of the D(3) pharmacophore and are expected to lead to novel approaches for the treatment of schizophrenia.
Assuntos
Antagonistas de Dopamina/química , Antagonistas de Dopamina/farmacologia , Pirimidinonas/química , Pirimidinonas/farmacologia , Receptores de Dopamina D3/antagonistas & inibidores , Disponibilidade Biológica , Antagonistas de Dopamina/síntese química , Humanos , Microssomos Hepáticos/metabolismo , Pirimidinonas/síntese química , Relação Estrutura-AtividadeRESUMO
The advent of large-scale NMR-based screening has enabled new strategies for the design of novel, potent inhibitors of therapeutic targets. In particular, fragment-based strategies, in which molecular portions of the final high-affinity ligand are experimentally identified prior to chemical synthesis, have found widespread utility. This chapter will discuss some of the practical considerations for identifying and utilizing these fragment leads in drug design, with special emphasis on some of the lessons learned from more than a decade of industry experience.
Assuntos
Desenho de Fármacos , Espectroscopia de Ressonância Magnética/métodos , Ligantes , Inibidores de Metaloproteinases de MatrizRESUMO
1,2,4-Oxadiazoles can be rapidly and efficiently synthesized from a variety of readily available carboxylic acids and amidoximes using either method A or method B. The use of commercially available polymer-supported reagents combined with microwave heating resulted in high yields and purities of the product 1,2,4-oxadiazoles in an expeditious manner. [structure: see text]
Assuntos
Ácidos Carboxílicos/química , Micro-Ondas , Oxidiazóis/síntese química , Oximas/química , Catálise , Indicadores e Reagentes , Estrutura Molecular , Oxidiazóis/análiseRESUMO
A series of non-amide-linked 6-substituted-2-naphthamidine urokinase plasminogen activator (uPA) inhibitors are described. These compounds possess excellent binding activities and selectivities with significantly improved pharmacokinetic profiles versus previously described amide-linked inhibitors.
Assuntos
Naftalenos/farmacocinética , Inativadores de Plasminogênio/farmacocinética , Ativador de Plasminogênio Tipo Uroquinase/antagonistas & inibidores , Modelos Moleculares , Naftalenos/química , Inativadores de Plasminogênio/química , Especificidade por SubstratoRESUMO
A rapid and efficient Suzuki coupling protocol has been developed utilizing polymer-supported palladium catalysts and microwave irradiation. It is also shown that solid-phase extraction of excess boronic acids can be rapidly and conveniently accomplished by utilization of a silica-supported carbonate base. [reaction: see text]
RESUMO
Antibacterial SAR for a series of macrolides derived from erythromycin A that are potent LHRH antagonists was developed in an attempt to eliminate the antibiotic activities of these compounds. Increasing the size of the alkyl substituents on the desosamine 3'-amine resulted in potent LHRH antagonists that were inactive against staphylococcal bacteria strains, and were significantly (>10-fold) less active against streptococcal bacteria strains. Complete elimination of antibacterial activities could be achieved by replacement of one or both methyl groups on the 3'-amine with a large alkyl substituent.
Assuntos
Antibacterianos/química , Antibacterianos/metabolismo , Eritromicina/química , Eritromicina/metabolismo , Hormônio Liberador de Gonadotropina/antagonistas & inibidores , Hormônio Liberador de Gonadotropina/metabolismo , Animais , Células CHO , Cricetinae , Humanos , Testes de Sensibilidade Microbiana , Ligação Proteica/fisiologia , Staphylococcus/efeitos dos fármacos , Staphylococcus/crescimento & desenvolvimento , Streptococcus/efeitos dos fármacos , Streptococcus/crescimento & desenvolvimento , Relação Estrutura-AtividadeRESUMO
[reaction: see text] The application of microwave heating to a polymer-assisted solution-phase (PASP) synthesis technique has been utilized to develop a rapid and efficient protocol for the solution-phase synthesis of amides from either amine or carboxylic acid cores.