RESUMO
Parathyroid hormone (PTH) is an effective bone anabolic agent. However, only when administered by daily sc injections exposure of short duration is achieved, a prerequisite for an anabolic response. Instead of applying exogenous PTH, mobilization of endogenous stores of the hormone can be envisaged. The secretion of PTH stored in the parathyroid glands is mediated by a calcium sensing receptor (CaSR) a GPCR localized at the cell surface. Antagonists of CaSR (calcilytics) mimic a state of hypocalcaemia and stimulate PTH release to the bloodstream. Screening of the internal compound collection for inhibition of CaSR signaling function afforded 2a. In vitro potency could be improved >1000 fold by optimization of its chemical structure. The binding mode of our compounds was predicted based on molecular modeling and confirmed by testing with mutated receptors. While the compounds readily induced PTH release after iv application a special formulation was needed for oral activity. The required profile was achieved by using microemulsions. Excellent PK/PD correlation was found in rats and dogs. High levels of PTH were reached in plasma within minutes which reverted to baseline in about 1-2 h in both species.
Assuntos
Conservadores da Densidade Óssea/síntese química , Hormônio Paratireóideo/metabolismo , Quinazolinonas/síntese química , Receptores de Detecção de Cálcio/metabolismo , Administração Oral , Animais , Conservadores da Densidade Óssea/administração & dosagem , Conservadores da Densidade Óssea/química , Conservadores da Densidade Óssea/farmacocinética , Cães , Concentração Inibidora 50 , Masculino , Quinazolinonas/administração & dosagem , Quinazolinonas/química , Quinazolinonas/farmacocinética , Ratos , Ratos Wistar , Receptores de Detecção de Cálcio/antagonistas & inibidores , Receptores de Detecção de Cálcio/genética , Relação Estrutura-AtividadeRESUMO
The preparation of tablets by the melt granulation process was investigated to enhance chemical stability of a highly water-soluble drug substance, dipeptidylpeptidase IV (DPP-IV) inhibitor (Compound I), that is susceptible to degradation in presence of moisture. Melt granulation with a lipophilic binder (hydrogenated castor oil; Cutina HR) improved the stability of the drug, while still maintaining immediate-release characteristics of the drug product. The drug to binder ratio was shown to impact the degradation behavior of the drug product. With higher binder levels, the sensitivity of the drug to degradation under humidity conditions decreased. It is postulated that the lipophilic binder coated drug particles at the surface protecting them from the influence of moisture. The granules had good flow properties and good compressibility and tablets prepared from them exhibited low weight variation and low friability.
