RESUMO
SAR of lead benzothiophene H(1)-antihistamine 2 was explored to identify backup candidates with suitable pharmacokinetic profiles for an insomnia program. Several potent and selective H(1)-antihistamines with a range of projected half-lives in humans were identified. Compound 16d had a suitable human half-life as demonstrated in a human microdose study, but variability in pharmacokinetic profile, attributed to metabolic clearance, prevented further development of this compound. Compound 28b demonstrated lower predicted clearance in preclinical studies, and may represent a more suitable backup compound.
Assuntos
Antagonistas dos Receptores Histamínicos H1/farmacologia , Antagonistas dos Receptores Histamínicos H1/farmacocinética , Distúrbios do Início e da Manutenção do Sono/tratamento farmacológico , Tiofenos/farmacologia , Tiofenos/farmacocinética , Antagonistas dos Receptores Histamínicos H1/química , Antagonistas dos Receptores Histamínicos H1/uso terapêutico , Humanos , Receptores Histamínicos H1/metabolismo , Relação Estrutura-Atividade , Tiofenos/química , Tiofenos/uso terapêuticoRESUMO
Derivatives of milnacipran were synthesized and studied as monoamine transporter inhibitors. Potent analogs were discovered at NET (9k) and at both NET and SERT (9s and 9u). A pharmacophore model was established based on the conformational analysis of milnacipran in aqueous solution using NMR techniques and was consistent with the SAR results.
Assuntos
Ciclopropanos/química , Ciclopropanos/farmacologia , Proteínas Vesiculares de Transporte de Monoamina/antagonistas & inibidores , Acetamidas/química , Acetamidas/farmacologia , Alquilação , Amidas/química , Amidas/farmacologia , Indóis/química , Indóis/farmacologia , Milnaciprano , Modelos Moleculares , Conformação Molecular , Ressonância Magnética Nuclear Biomolecular , Estereoisomerismo , Relação Estrutura-Atividade , Proteínas Vesiculares de Transporte de Monoamina/químicaRESUMO
Compounds with various activities and selectivities were discovered through structure-activity relationship studies of bicifadine analogs as monoamine transporter inhibitors. The norepinephrine-selective 2-thienyl compound S-6j was efficacious in a rodent pain model.
Assuntos
Compostos Bicíclicos Heterocíclicos com Pontes/química , Compostos Bicíclicos Heterocíclicos com Pontes/farmacologia , Proteínas de Transporte de Neurotransmissores/química , Animais , Células CACO-2 , Química Farmacêutica/métodos , Desenho de Fármacos , Humanos , Concentração Inibidora 50 , Proteínas de Membrana Transportadoras/química , Proteínas de Membrana Transportadoras/farmacologia , Modelos Químicos , Neurotransmissores/metabolismo , Proteínas de Transporte de Neurotransmissores/antagonistas & inibidores , Norepinefrina/química , Dor , Ratos , Relação Estrutura-AtividadeRESUMO
A series of milnacipran analogs were synthesized and studied as monoamine transporter inhibitors, and several potent compounds with moderate lipophilicity were identified from the 1S,2R-isomers. Thus, 15l exhibited IC(50) values of 1.7nM at NET and 25nM at SERT, which were, respectively, 20- and 13-fold more potent than 1S,2R-milnacipran 1-II.
Assuntos
Antidepressivos/síntese química , Antidepressivos/farmacologia , Ciclopropanos/síntese química , Ciclopropanos/farmacologia , Norepinefrina/antagonistas & inibidores , Inibidores Seletivos de Recaptação de Serotonina/síntese química , Antidepressivos/química , Técnicas de Química Combinatória , Ciclopropanos/química , Humanos , Concentração Inibidora 50 , Milnaciprano , Estrutura Molecular , Inibidores Seletivos de Recaptação de Serotonina/química , Inibidores Seletivos de Recaptação de Serotonina/farmacologia , Estereoisomerismo , Relação Estrutura-AtividadeRESUMO
A series of milnacipran analogs containing a heteroaromatic group were synthesized and studied as monoamine transporter inhibitors. Many compounds exhibited higher potency than milnacipran at NET and NET/SERT with no significant change in lipophilicity. For example, compound R-26f was about 10-fold more potent than milnacipran with IC(50) values of 8.7 and 26nM at NET and SERT, respectively.
Assuntos
Ciclopropanos/síntese química , Ciclopropanos/farmacologia , Proteínas da Membrana Plasmática de Transporte de Norepinefrina/antagonistas & inibidores , Inibidores Seletivos de Recaptação de Serotonina/síntese química , Inibidores Seletivos de Recaptação de Serotonina/farmacologia , Técnicas de Química Combinatória , Ciclopropanos/química , Humanos , Milnaciprano , Estrutura Molecular , Norepinefrina/metabolismo , Proteínas da Membrana Plasmática de Transporte de Serotonina/metabolismo , Inibidores Seletivos de Recaptação de Serotonina/química , Relação Estrutura-AtividadeRESUMO
We describe a new strategy for the preparation of catalytic antibodies based on a two-step procedure. Firstly, monoclonal antibodies are selected only if displaying the following binding features: binding both the substrate and a reactive group in such a way that the two groups are in a reactive position towards each other. Secondly, the selected monoclonal antibodies (mAbs) are chemically engineered by covalently binding the reactive group into the binding pocket of the antibody. Using previously isolated monoclonal antibodies, we have focused our studies on the control of this second step.
Assuntos
Acetilcolinesterase/imunologia , Anticorpos Catalíticos/biossíntese , Anticorpos Monoclonais/biossíntese , Animais , Anticorpos Catalíticos/metabolismo , Anticorpos Monoclonais/metabolismoRESUMO
Analogues of the known H(1)-antihistamine R-dimethindene were profiled as potential agents for the treatment of insomnia. Several highly selective compounds were efficacious in rodent sleep models. On the basis of overall profile, indene 1d and benzothiophene 2a had pharmacokinetic properties suitable for evaluation in night time dosing. Compound 2a did not show an in vivo cardiovascular effect from weak hERG channel inhibition.
Assuntos
Antagonistas dos Receptores Histamínicos H1/farmacologia , Antagonistas dos Receptores Histamínicos H1/uso terapêutico , Distúrbios do Início e da Manutenção do Sono/tratamento farmacológico , Animais , Encéfalo/metabolismo , Dimetideno/metabolismo , Dimetideno/farmacocinética , Dimetideno/farmacologia , Dimetideno/uso terapêutico , Eletroencefalografia/efeitos dos fármacos , Canais de Potássio Éter-A-Go-Go/antagonistas & inibidores , Antagonistas dos Receptores Histamínicos H1/metabolismo , Antagonistas dos Receptores Histamínicos H1/farmacocinética , Humanos , Ratos , Receptores Muscarínicos/metabolismo , Sono/efeitos dos fármacos , Especificidade por SubstratoRESUMO
Thien-2-yl 1S,2R-milnacipran analogues were synthesized and characterized as norepinephrine/serotonin transporter inhibitors. These compounds possessed higher potencies than 1S,2R-milnacipran (2R-1) while maintaining low molecular weight and moderate lipophilicity, which are the important features for the pharmacological and pharmacokinetic characteristics of milnacipran (1). Thus, compound 5c exhibited IC50 values of 2.3 and 32 nM, respectively, at NET and SERT, which were more than 10-fold better than those of 1 (NET IC50 = 77 nM, SERT IC50 = 420 nM). Moreover, 5c achieved the same efficacy as 1, but with much lower doses, in a rodent spinal nerve ligation pain model. In addition, 5c displayed desirable pharmacokinetic properties in several species, including high oral availability and significant brain penetration.