RESUMEN
Once-daily s.c. administration of either human parathyroid hormone (PTH)-(1-84) or recombinant human PTH-(1-34) provides for dramatic increases in bone mass in women with postmenopausal osteoporosis. We initiated a program to discover orally bioavailable small molecule equivalents of these peptides. A traditional high-throughput screening approach using cAMP activation of the PTH/PTH-related peptide receptor (PPR) as a readout failed to provide any lead compounds. Accordingly, we designed a new screen for this receptor that used a modified N-terminal fragment of PTH as a probe for small molecule binding to the transmembrane region of the PPR, driven by the assumption that the pharmacological properties (agonist/antagonist) of compounds that bound to this putative signaling domain of the PPR could be altered by chemical modification. We developed DPC-AJ1951, a 14 amino acid peptide that acts as a potent agonist of the PPR, and characterized its activity in ex vivo and in vivo assays of bone resorption. In addition, we studied its ability to initiate gene transcription by using microarray technology. Together, these experiments indicated that the highly modified 14 amino acid peptide induces qualitatively similar biological responses to those produced by PTH-(1-34), albeit with lower potency relative to the parent peptide. Encouraged by these data, we performed a screen of a small compound collection by using DPC-AJ1951 as the ligand. These studies led to the identification of the benzoxazepinone SW106, a previously unrecognized small molecule antagonist for the PPR. The binding of SW106 to the PPR was rationalized by using a homology receptor model.
Asunto(s)
Sondas Moleculares/fisiología , Oxazepinas/farmacología , Hormona Paratiroidea/fisiología , Fragmentos de Péptidos/fisiología , Receptor de Hormona Paratiroídea Tipo 1/antagonistas & inhibidores , Secuencia de Aminoácidos , Animales , Unión Competitiva , Línea Celular , Evaluación Preclínica de Medicamentos , Humanos , Masculino , Técnicas de Sonda Molecular , Datos de Secuencia Molecular , Oxazepinas/agonistas , Hormona Paratiroidea/agonistas , Hormona Paratiroidea/metabolismo , Fragmentos de Péptidos/agonistas , Fragmentos de Péptidos/metabolismo , Unión Proteica , Ratas , Ratas Sprague-Dawley , Receptor de Hormona Paratiroídea Tipo 1/agonistas , Receptor de Hormona Paratiroídea Tipo 1/metabolismoRESUMEN
The synthesis, evaluation, and structure-activity relationships of a series of succinoyl lactam inhibitors of the Alzheimer's disease gamma-secretase are described. Beginning with a screening hit with broad proteinase activity, optimization provided compounds with both high selectivity for inhibition of gamma-secretase and high potency in cellular assays of A beta reduction. The SAR and early in vivo properties of this series of inhibitors will be presented.
Asunto(s)
Caprolactama/química , Endopeptidasas/efectos de los fármacos , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/farmacología , Succinatos/química , Enfermedad de Alzheimer/tratamiento farmacológico , Enfermedad de Alzheimer/enzimología , Secretasas de la Proteína Precursora del Amiloide , Animales , Ácido Aspártico Endopeptidasas , Caprolactama/análogos & derivados , Línea Celular , Perros , Diseño de Fármacos , Evaluación Preclínica de Medicamentos , Endopeptidasas/química , Inhibidores Enzimáticos/química , Humanos , Conformación Molecular , Estereoisomerismo , Relación Estructura-ActividadRESUMEN
A series of cis-1(S)2(R)-amino-2-indanol based compounds with a biphenylmethyl group at the P1' position was found to be potent aggrecanase inhibitors. Both compounds 2j and 2n possessed very high aggrecanase affinity (IC(50)=1.5nM), and showed excellent selectivity over MMP-1 and MMP-9, with moderate selectivity against MMP-2.