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1.
Bioorg Med Chem Lett ; 24(9): 2168-72, 2014 May 01.
Artículo en Inglés | MEDLINE | ID: mdl-24685543

RESUMEN

Follicle-stimulating hormone (FSH), acting on its receptor (FSHR), plays a pivotal role in the stimulation of follicular development and maturation. Multiple injections of protein formulations are used during clinical protocols for ovulation induction and for in vitro fertilization that are followed by a selection of assisted reproductive technologies. In order to increase patient convenience and compliance several research groups have searched for orally bioavailable FSH mimetics for innovative fertility medicines. We report here the discovery of a series of substituted benzamides as positive allosteric modulators (PAM) targeting FSHR. Optimization of this series has led to enhanced activity in primary rat granulosa cells, as well as remarkable selectivity against the closely related luteinizing hormone receptor (LHR) and thyroid stimulating hormone receptor (TSHR). Two modulators, 9j and 9k, showed promising in vitro and pharmacokinetic profiles.


Asunto(s)
Regulación Alostérica/efectos de los fármacos , Benzamidas/química , Benzamidas/farmacología , Hormona Folículo Estimulante/metabolismo , Animales , Células CHO , Células Cultivadas , Cricetulus , Femenino , Hormona Folículo Estimulante/agonistas , Células de la Granulosa/efectos de los fármacos , Células de la Granulosa/metabolismo , Humanos , Ratas
2.
J Med Chem ; 56(9): 3710-24, 2013 May 09.
Artículo en Inglés | MEDLINE | ID: mdl-23631755

RESUMEN

We characterized the mechanism and pharmacodynamics of five structurally distinct inhibitors of d-amino acid oxidase. All inhibitors bound the oxidized form of human enzyme with affinity slightly higher than that of benzoate (Kd ≈ 2-4 µM). Stopped-flow experiments showed that pyrrole-based inhibitors possessed high affinity (Kd ≈ 100-200 nM) and slow release kinetics (k < 0.01 s(-1)) in the presence of substrate, while inhibitors with pendent aromatic groups altered conformations of the active site lid, as evidenced by X-ray crystallography, and showed slower kinetics of association. Rigid bioisosteres of benzoic acid induced a closed-lid conformation, had slower release in the presence of substrate, and were more potent than benzoate. Steady-state d-serine concentrations were described in a PK/PD model, and competition for d-serine sites on NMDA receptors was demonstrated in vivo. DAAO inhibition increased the spatiotemporal influence of glial-derived d-serine, suggesting localized effects on neuronal circuits where DAAO can exert a neuromodulatory role.


Asunto(s)
D-Aminoácido Oxidasa/antagonistas & inhibidores , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/farmacología , Bibliotecas de Moléculas Pequeñas/química , Bibliotecas de Moléculas Pequeñas/farmacología , Animales , Conducta Animal/efectos de los fármacos , Unión Competitiva , Dominio Catalítico , D-Aminoácido Oxidasa/química , D-Aminoácido Oxidasa/metabolismo , Inhibidores Enzimáticos/metabolismo , Inhibidores Enzimáticos/farmacocinética , Glicina/metabolismo , Humanos , Cinética , Masculino , Simulación del Acoplamiento Molecular , Neuroglía/efectos de los fármacos , Neuroglía/metabolismo , Ratas , Ratas Sprague-Dawley , Serina/biosíntesis , Bibliotecas de Moléculas Pequeñas/metabolismo , Bibliotecas de Moléculas Pequeñas/farmacocinética
3.
J Med Chem ; 46(12): 2467-73, 2003 Jun 05.
Artículo en Inglés | MEDLINE | ID: mdl-12773050

RESUMEN

A novel piperidine series of farnesyltransferase (FTase) inhibitors is described. Systematic medicinal chemistry studies starting with the lead compound, discovered from a 5-nitropiperidin-2-one combinatorial library, resulted in a potent series of novel FTase inhibitors. We found that all of four substituents of the piperidine core played an important role for FTase inhibition. A 10-fold increase in potency was observed by changing the piperidine-2-one core to the corresponding piperidine core. This class of compounds was found to inhibit farnesyltransferase in a Ras competitive manner. Optical resolution of several potent inhibitors revealed that the (+)-enantiomers showed potent farnesyltransferase inhibition. (+)-8 inhibited FTase with an IC(50) of 1.9 nM.


Asunto(s)
Transferasas Alquil y Aril/antagonistas & inhibidores , Inhibidores Enzimáticos/síntesis química , Piperidinas/síntesis química , Transferasas Alquil y Aril/química , Animales , Bovinos , Cromatografía Líquida de Alta Presión , Técnicas Químicas Combinatorias , Cristalografía por Rayos X , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/farmacología , Farnesiltransferasa , Humanos , Cinética , Espectroscopía de Resonancia Magnética , Piperidinas/química , Piperidinas/farmacología , Estereoisomerismo , Relación Estructura-Actividad , Células Tumorales Cultivadas , Proteínas ras/metabolismo
4.
J Med Chem ; 45(12): 2624-43, 2002 Jun 06.
Artículo en Inglés | MEDLINE | ID: mdl-12036372

RESUMEN

A series of analogues of the protein kinase C (PKC) inhibitory natural product balanol which bear modified benzophenone subunits are described. The analogues were designed with the goal of uncovering structure-activity features that could be used in the development of PKC inhibitors with a reduced polar character compared to balanol itself. The results of these studies suggest that most of the benzophenone features found in the natural product are important for obtaining potent PKC inhibitory compounds. However, several modifications were found to lead to selective inhibitors of the related enzyme protein kinase A (PKA), and several specific modifications to the polar structural elements of the benzophenone were found to provide potent PKC inhibitors. In particular, it was found that replacement of the benzophenone carboxylate with bioisosteric equivalents could lead to potent analogues. Further, a tolerance for lipophilic substituents on the terminal benzophenone ring was uncovered. These results are discussed in light of recently available structural information for PKA.


Asunto(s)
Azepinas/síntesis química , Benzofenonas/síntesis química , Inhibidores Enzimáticos/síntesis química , Hidroxibenzoatos/síntesis química , Proteína Quinasa C/antagonistas & inhibidores , Azepinas/química , Benzofenonas/química , Inhibidores Enzimáticos/química , Humanos , Hidroxibenzoatos/química , Isoenzimas/antagonistas & inhibidores , Relación Estructura-Actividad
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