RESUMEN
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).
Asunto(s)
Receptores Nicotínicos , Receptor Nicotínico de Acetilcolina alfa 7 , Receptor Nicotínico de Acetilcolina alfa 7/metabolismo , Regulación Alostérica , Receptores Nicotínicos/metabolismo , Indoles/farmacologíaRESUMEN
HTS campaign of the corporate compound collection resulted in a novel, oxalic acid diamide scaffold of α7 nACh receptor positive allosteric modulators. During the hit expansion, several derivatives, such as 4, 11, 17 demonstrated not only high in vitro potency, but also in vivo efficacy in the mouse place recognition test. The advanced hit molecule 11 was further optimized by the elimination of the putatively mutagenic aromatic-amine building block that resulted in a novel, aminomethylindole compound family. The most balanced physico-chemical and pharmacological profile was found in case of compound 55. Docking study revealed an intersubunit binding site to be the most probable for our compounds. 55 demonstrated favorable cognitive enhancing profile not only in scopolamine-induced amnesia (place recognition test in mice) but also in natural forgetting (novel object recognition test in rats). Compound 55 was, furthermore, active in a cognitive paradigm of high translational value, namely in the rat touch screen visual discrimination test. Therefore, 55 was selected as a lead compound for further optimization. Based on the obtained favorable results, the invented aminomethylindole cluster may provide a viable approach for cognitive enhancement through positive allosteric modulation of α7 nAChRs.
Asunto(s)
Amidas/farmacología , Descubrimiento de Drogas , Ensayos Analíticos de Alto Rendimiento , Ácido Oxálico/farmacología , Receptor Nicotínico de Acetilcolina alfa 7/metabolismo , Regulación Alostérica/efectos de los fármacos , Amidas/síntesis química , Amidas/química , Animales , Relación Dosis-Respuesta a Droga , Humanos , Masculino , Estructura Molecular , Ácido Oxálico/síntesis química , Ácido Oxálico/química , Ratas , Ratas Wistar , Relación Estructura-ActividadRESUMEN
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.
Asunto(s)
4-Quinolonas/química , Antagonistas del Receptor Purinérgico P2X/química , Quinazolinonas/química , Receptores Purinérgicos P2X3/metabolismo , 4-Quinolonas/síntesis química , 4-Quinolonas/metabolismo , Adenosina Trifosfato/metabolismo , Humanos , Concentración 50 Inhibidora , Unión Proteica , Antagonistas del Receptor Purinérgico P2X/síntesis química , Antagonistas del Receptor Purinérgico P2X/metabolismo , Quinazolinonas/metabolismo , Receptores Purinérgicos P2X3/química , Relación Estructura-ActividadRESUMEN
Medicinal chemistry optimization of an impurity isolated during the scale-up synthesis of a pyridylsulfonamide type dopamine D(3)/D(2) compound (1) led to a series of new piperazine derivatives having affinity to both dopamine D(3) and D(2) receptors. Several members of this group showed excellent pharmacokinetic and pharmacodynamic properties as demonstrated by outstanding activities in different antipsychotic tests. The most promising representative, 2m (cariprazine) had good absorption, excellent brain penetration and advantageous safety profile. Based on its successful clinical development we are looking forward to the NDA filing of cariprazine in 2012.
Asunto(s)
Antipsicóticos/farmacología , Piperazinas/farmacología , Receptores de Dopamina D2/efectos de los fármacos , Receptores de Dopamina D4/efectos de los fármacos , Animales , Antipsicóticos/farmacocinética , Área Bajo la Curva , Humanos , Piperazinas/farmacocinética , RatasRESUMEN
A new series of quinolinyl- and phenantridinyl-acetamides were synthesizer and evaluated against bradykinin B1 receptor. In vitro metabolic stability data were reported for the key compounds.The analgesic effect of compound 20 from the phenantridine series was proved in-vivo.
Asunto(s)
Acetamidas/síntesis química , Antagonistas del Receptor de Bradiquinina B1 , Fenantrenos/síntesis química , Quinolinas/síntesis química , Acetamidas/farmacología , Analgésicos/síntesis química , Analgésicos/farmacología , Línea Celular , Humanos , Metabolismo , Fenantrenos/farmacología , Quinolinas/farmacologíaRESUMEN
A novel series of arylsulfonamides was prepared either by automated parallel or by traditional solution-phase synthesis. Several members of this compound library were identified as high-affinity dopamine D3 and D2 receptor ligands. The most interesting representative, compound 2, showed potent antipsychotic behaviour coupled with a beneficial cognitive and EPS profile.
Asunto(s)
Antipsicóticos/síntesis química , Antipsicóticos/farmacología , Cognición/efectos de los fármacos , Receptores de Dopamina D2/metabolismo , Receptores de Dopamina D3/metabolismo , Sulfonamidas/síntesis química , Sulfonamidas/farmacología , Animales , Antipsicóticos/metabolismo , Apomorfina/farmacología , Reacción de Prevención/efectos de los fármacos , Unión Competitiva/efectos de los fármacos , Disponibilidad Biológica , Encéfalo/metabolismo , Catalepsia/inducido químicamente , Humanos , Indicadores y Reactivos , Masculino , Aprendizaje por Laberinto/efectos de los fármacos , Trastornos de la Memoria/inducido químicamente , Relación Estructura-Actividad Cuantitativa , Ratas , Ratas Wistar , Conducta Estereotipada/efectos de los fármacos , Sulfonamidas/metabolismoRESUMEN
A chemical and biological information system with a Web-based easy-to-use interface and corresponding databases has been developed. The constructed system incorporates all chemical, numerical and textual data related to the chemical compounds, including numerical biological screen results. Users can search the database by traditional textual/numerical and/or substructure or similarity queries through the web interface. To build our chemical database management system, we utilized existing IT components such as ORACLE or Tripos SYBYL for database management and Zope application server for the web interface. We chose Linux as the main platform, however, almost every component can be used under various operating systems.
Asunto(s)
Sistemas de Administración de Bases de Datos , Diseño de Fármacos , Lenguajes de Programación , Biología , Fenómenos Químicos , Química , Sistemas de Administración de Bases de Datos/economía , Almacenamiento y Recuperación de la Información/economía , Internet , Interfaz Usuario-ComputadorRESUMEN
A brief survey is given on the synthesis and structure elucidation for dihydro-1,2,4-triazines. The relative stability of nine possible dihydro-1,2,4-triazines and three dihydrotriazinium cations is studied at HF, MP2, generalized gradient approximation DFT, and CBS-4 levels of theory. The structural consequences of the inclusion of the electron correlation are also given. We attempt to rationalize the experimental findings using high-quality theoretical results. The quantum chemical calculations support that the most stable isomer is the 2,5-dihydro-1,2,4-triazine and all the other relatively stable isomers have been experimentally identified correctly. Several experimental papers report structures that have been proved to be nonexistent. These structures have energy that is too high according to the best-quality calculations.