RESUMO
The synthesis and SAR of a novel class of spirobenzofuranpiperidinyl-derived alkanoic acids 6-34 as sphingosine S1P5 receptor agonists are described. The target compounds generally elicit high S1P5 receptor agonistic potencies and in general are selective against both S1P1 and S1P3 receptor subtypes. The key compound 32 shows a high bioavailability of 73% and a CNS/plasma ratio of 0.8 after oral administration in rats.
Assuntos
Benzofuranos/farmacologia , Receptores de Lisoesfingolipídeo/agonistas , Administração Oral , Animais , Benzofuranos/química , Disponibilidade Biológica , Relação Dose-Resposta a Droga , Humanos , Simulação de Acoplamento Molecular , Estrutura Molecular , Ratos , Relação Estrutura-AtividadeRESUMO
The discovery of non-basic N'-(arylsulfonyl)pyrazoline-1-carboxamidines as 5-HT6 antagonists with unique structural features was recently disclosed. Here we describe how this structural class was further developed by addressing an unexplored interaction site of the 5-HT6 receptor. Compound 13 resulting from this effort is a highly potent and selective 5-HT6 antagonist with improved metabolic stability. It is furthermore devoid of hERG affinity. Despite its modest CNS/plasma ratio, a high brain free fraction ensured substantial exposure to allow for rodent cognition studies.
Assuntos
Pirazóis/farmacologia , Receptores de Serotonina/metabolismo , Antagonistas da Serotonina/farmacologia , Sulfonamidas/farmacologia , Sítios de Ligação/efeitos dos fármacos , Relação Dose-Resposta a Droga , Humanos , Simulação de Acoplamento Molecular , Estrutura Molecular , Pirazóis/síntese química , Pirazóis/química , Antagonistas da Serotonina/síntese química , Antagonistas da Serotonina/química , Relação Estrutura-Atividade , Sulfonamidas/síntese química , Sulfonamidas/químicaRESUMO
The synthesis, structure-activity relationship (SAR) studies and intramolecular hydrogen bonding pattern of 1,3,5-trisubstituted 4,5-dihydropyrazoles are described. The target compounds 6-18 represent a novel class of potent and selective CB(1) receptor antagonists. Based on X-ray diffraction data, the orally active 17 is shown to elicit a different intramolecular H-bonding mode as compared to ibipinabant (3) and SLV330 (4).
Assuntos
Fármacos Antiobesidade/síntese química , Pirazóis/síntese química , Receptor CB1 de Canabinoide/antagonistas & inibidores , Sulfonamidas/síntese química , Administração Oral , Animais , Fármacos Antiobesidade/química , Fármacos Antiobesidade/farmacologia , Sítios de Ligação , Cristalografia por Raios X , Humanos , Ligação de Hidrogênio , Conformação Molecular , Pirazóis/química , Pirazóis/farmacologia , Ratos , Receptor CB1 de Canabinoide/metabolismo , Relação Estrutura-Atividade , Sulfonamidas/química , Sulfonamidas/farmacologiaRESUMO
The synthesis and structure-activity relationship studies of imidazoles are described. The target compounds 6-20 represent a novel chemotype of potent and CB(2)/CB(1) selective cannabinoid CB(2) receptor antagonists/inverse agonists with very high binding efficiencies in combination with favourable logP and calculated polar surface area values. Compound 12 exhibited the highest CB(2) receptor affinity (K(i)=1.03 nM) in this series, as well as the highest CB(2)/CB(1) subtype selectivity (>9708-fold).
Assuntos
Imidazóis/síntese química , Imidazóis/metabolismo , Receptor CB2 de Canabinoide/antagonistas & inibidores , Receptor CB2 de Canabinoide/metabolismo , Animais , Células CHO , Canabinoides/antagonistas & inibidores , Canabinoides/metabolismo , Cricetinae , Cricetulus , Relação Dose-Resposta a Droga , Humanos , Ligação Proteica/fisiologia , Relação Estrutura-AtividadeRESUMO
The synthesis and structure-activity relationship studies of 1,4,5,6-tetrahydropyridazines are described. The target compounds 3-5 represent a novel class of potent and selective CB1 receptor antagonists.
Assuntos
Piridazinas/síntese química , Receptor CB1 de Canabinoide/antagonistas & inibidores , Animais , Células CHO , Cricetinae , Cricetulus , Humanos , Piridazinas/química , Piridazinas/farmacologia , Receptor CB1 de Canabinoide/metabolismo , Relação Estrutura-AtividadeRESUMO
We have investigated a series of 7-azaindoles as potential partial agonists of the alpha4beta2 nicotinic acetylcholine receptor (nAChR). Three series of 7-azaindole derivatives have been synthesized and evaluated for rat brain neuronal nicotinic receptor affinity and functional activity. Compound (+)-51 exhibited the most potent nAChR binding (Ki = 10 nM). Compound 30A demonstrated both moderate binding affinity and partial agonist potency, thus representing a promising lead for the indications of cognition and smoking cessation.
Assuntos
Indóis/química , Indóis/farmacologia , Agonistas Nicotínicos/química , Agonistas Nicotínicos/farmacologia , Alcaloides/química , Alcaloides/metabolismo , Animais , Compostos Aza/síntese química , Compostos Aza/química , Compostos Aza/farmacocinética , Compostos Aza/farmacologia , Azocinas/química , Azocinas/metabolismo , Encéfalo/metabolismo , Indóis/síntese química , Indóis/farmacocinética , Cinética , Neurônios/metabolismo , Agonistas Nicotínicos/síntese química , Agonistas Nicotínicos/farmacocinética , Quinolizinas/química , Quinolizinas/metabolismo , Ensaio Radioligante , Ratos , Receptores Nicotínicos/química , Receptores Nicotínicos/metabolismoRESUMO
A series of novel bicyclic 1-heteroaryl-4-[omega-(1H-indol-3-yl)alkyl]piperazines was synthesized and evaluated on binding to dopamine D(2) receptors and serotonin reuptake sites. This class of compounds proved to be potent in vitro dopamine D(2) receptor antagonists and in addition were highly active as serotonin reuptake inhibitors. Some key representatives showed potent pharmacological in vivo activities after oral dosing in both the antagonism of apomorphine-induced climbing and the potentiation of 5-HTP-induced behavior in mice. On the basis of the preclinical data, 8-{4-[3-(5-fluoro-1H-indol-3-yl)propyl]piperazin-1-yl}-4H-benzo[1,4]oxazin-(R)-2-methyl-3-one (45c, SLV314) was selected for clinical development. In vitro and in vivo studies revealed that 45c has favorable pharmacokinetic properties and a high CNS-plasma ratio. Molecular modeling studies showed that the bifunctional activity of 45c can be explained by its ability to adopt two different conformations fitting either the dopamine D(2) receptor pharmacophore or the serotonin transporter pharmacophore.
Assuntos
Antipsicóticos/síntese química , Benzoxazinas/síntese química , Antagonistas dos Receptores de Dopamina D2 , Indóis/síntese química , Piperazinas/síntese química , Inibidores Seletivos de Recaptação de Serotonina/síntese química , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/metabolismo , Animais , Antipsicóticos/farmacocinética , Antipsicóticos/farmacologia , Benzoxazinas/farmacocinética , Benzoxazinas/farmacologia , Transporte Biológico , Células CHO , Linhagem Celular , Cricetinae , Cricetulus , Indóis/farmacocinética , Indóis/farmacologia , Masculino , Modelos Moleculares , Piperazinas/farmacocinética , Piperazinas/farmacologia , Ratos , Inibidores Seletivos de Recaptação de Serotonina/farmacocinética , Inibidores Seletivos de Recaptação de Serotonina/farmacologia , Relação Estrutura-AtividadeRESUMO
A series of novel 3,4-diarylpyrazolines was synthesized and evaluated in cannabinoid (hCB(1) and hCB(2)) receptor assays. The 3,4-diarylpyrazolines elicited potent in vitro CB(1) antagonistic activities and in general exhibited high CB(1) vs CB(2) receptor subtype selectivities. Some key representatives showed potent pharmacological in vivo activities after oral dosing in both a CB agonist-induced blood pressure model and a CB agonist-induced hypothermia model. Chiral separation of racemic 67, followed by crystallization and an X-ray diffraction study, elucidated the absolute configuration of the eutomer 80 (SLV319) at its C(4) position as 4S. Bioanalytical studies revealed a high CNS-plasma ratio for the development candidate 80. Molecular modeling studies showed a relatively close three-dimensional structural overlap between 80 and the known CB(1) receptor antagonist rimonabant (SR141716A). Further analysis of the X-ray diffraction data of 80 revealed the presence of an intramolecular hydrogen bond that was confirmed by computational methods. Computational models and X-ray diffraction data indicated a different intramolecular hydrogen bonding pattern in the in vivo inactive compound 6. In addition, X-ray diffraction studies of 6 revealed a tighter intermolecular packing than 80, which also may contribute to its poorer absorption in vivo. Replacement of the amidine -NH(2) moiety with a -NHCH(3) group proved to be the key change for gaining oral biovailability in this series of compounds leading to the identification of 80.