RESUMO
Solid preclinical evidence links vasopressin to social behavior in animals, so, extensive work has been initiated to find new vasopressin V1a receptor antagonists which can improve deteriorated social behavior in humans and can treat the core symptoms of autistic behavior, as well. Our aim was to identify new chemical entities with antagonizing effects on vasopressin V1a receptors. Starting from a moderately potent HTS hit (7), we identified a molecule (49) having nanomolar binding strength and functional activity, which is in the same range as the potency of clinically tested V1a antagonists.
Assuntos
Antagonistas dos Receptores de Hormônios Antidiuréticos/síntese química , Receptores de Vasopressinas/metabolismo , Transtornos do Comportamento Social/tratamento farmacológico , Ureia/síntese química , Antagonistas dos Receptores de Hormônios Antidiuréticos/farmacologia , Ensaios de Triagem em Larga Escala , Humanos , Concentração Inibidora 50 , Piperazina/química , Ligação Proteica , Piridinas/química , Quinolinas/química , Relação Estrutura-Atividade , Ureia/farmacologiaRESUMO
Purinergic P2X3 receptors are trimeric ligand-gated ion channels whose antagonism is an appealing yet challenging and not fully validated drug development idea. With the aim of identification of an orally active, potent human P2X3 receptor antagonist compound that can penetrate the central nervous system, the compound collection of Gedeon Richter was screened. A hit series of tricyclic compounds was subjected to a rapid, two-step optimization process focusing on increasing potency, improving metabolic stability and CNS penetrability. Attempts resulted in compound 65, a potential tool compound for testing P2X3 inhibitory effects in vivo.
Assuntos
Compostos Heterocíclicos com 3 Anéis/síntese química , Compostos Heterocíclicos/química , Mesilatos/síntese química , Antagonistas do Receptor Purinérgico P2X/química , Receptores Purinérgicos P2X3/metabolismo , Trifosfato de Adenosina/metabolismo , Avaliação Pré-Clínica de Medicamentos , Compostos Heterocíclicos com 3 Anéis/química , Humanos , Concentração Inibidora 50 , Mesilatos/química , Microssomos/metabolismo , Ligação Proteica , Antagonistas do Receptor Purinérgico P2X/síntese química , Antagonistas do Receptor Purinérgico P2X/metabolismo , Receptores Purinérgicos P2X3/química , Relação Estrutura-AtividadeRESUMO
Numerous potent P2X3 antagonists have been discovered and the therapeutic potential of P2X3 antagonism already comprises proof-of-concept data obtained in clinical trials with the most advanced compound. We have lately reported the discovery and optimization of thia-triaza-tricycle compounds with potent P2X3 antagonistic properties. This Letter describes the SAR of a back-up series containing a 4-oxo-quinazoline central ring. The discovery of the highly potent compounds 51 is presented.
Assuntos
4-Quinolonas/química , Antagonistas do Receptor Purinérgico P2X/química , Quinazolinonas/química , Receptores Purinérgicos P2X3/metabolismo , 4-Quinolonas/síntese química , 4-Quinolonas/metabolismo , Trifosfato de Adenosina/metabolismo , Humanos , Concentração Inibidora 50 , Ligação Proteica , Antagonistas do Receptor Purinérgico P2X/síntese química , Antagonistas do Receptor Purinérgico P2X/metabolismo , Quinazolinonas/metabolismo , Receptores Purinérgicos P2X3/química , Relação Estrutura-AtividadeRESUMO
Selecting a known HTS hit with the pyrazolo[1,5-a]pyrimidine core, our project was started from CMPPE, and its optimization was driven by a ligand-based pharmacophore model developed on the basis of published GABAB positive allosteric modulators (PAMs). Our primary goal was to improve the potency by finding new enthalpic interactions. Therefore, we included the lipophilic ligand efficiency (LLE or LipE) as an objective function in the optimization that led to a carboxylic acid derivative (34). This lead candidate offers the possibility to improve potency without drastically inflating the physicochemical properties. Although the discovery of the novel carboxyl feature was surprising, it turned out to be an important element of the GABAB PAM pharmacophore that can be perfectly explained based on the new protein structures. Rationalizing the binding mode of 34, we analyzed the intersubunit PAM binding site of GABAB receptor using the publicly available experimental structures.
RESUMO
During optimization of a previously identified lead compound, attempts were made to optimize the reactive indole structural element, the suboptimal metabolic stability, as well as the low kinetic solubility. It was concluded that the indole was important for in vitro activity. With the aim of further improvements, more thorough modifications were also carried out. As a result, a new chemotype (the azetidinespirochromone family) was identified, which proved to be 1 order of magnitude less lipophilic retaining the same high level of in vitro potency as the lead series itself, however, with improved metabolic stability and kinetic solubility. Compound 53 showed the most balanced physicochemical and pharmacological profile with significant in vivo efficacy in the scopolamine-induced amnesia test. Based on these promising results, cognitive enhancement through the positive modulation of α7 nAChRs appears to be a viable approach. Compound 53 was selected to be a preclinical development candidate (as RGH-560).