RESUMO
Subtle modifications were incorporated into the structure of clinical candidate 1. These changes were designed to maintain potency and selectivity while inducing changes in physical properties leading to improved pharmacokinetics in three species. This approach led to the identification of 4 as a potent, selective alphaVbeta3 receptor antagonist that was selected for clinical development based on an improved PK profile and efficacy demonstrated in an in vivo model of bone turnover.
Assuntos
Integrina alfaVbeta3/antagonistas & inibidores , Naftiridinas/química , Animais , Cães , Avaliação Pré-Clínica de Medicamentos/métodos , Humanos , Integrina alfaVbeta3/metabolismo , Macaca mulatta , Masculino , Naftiridinas/metabolismo , Naftiridinas/farmacologia , Ligação Proteica/efeitos dos fármacos , Ligação Proteica/fisiologia , RatosRESUMO
3-(S)-Pyrimidin-5-yl-9-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-nonanoic acid (5e) and 3-(S)-(methylpyrimidin-5-yl)-9-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-nonanoic acid (5f) were identified as potent and selective antagonists of the alpha(v)beta(3) receptor. These compounds have excellent in vitro profiles (IC(50) = 0.07 and 0.08 nM, respectively), significant unbound fractions in human plasma (6 and 4%), and good pharmacokinetics in rat, dog, and rhesus monkey. On the basis of the efficacy shown in an in vivo model of bone turnover following once-daily oral administration, these two compounds were selected for clinical development for the treatment of osteoporosis.
Assuntos
Integrinas/antagonistas & inibidores , Naftiridinas/farmacologia , Osteoporose/tratamento farmacológico , Receptores de Vitronectina/antagonistas & inibidores , Administração Oral , Animais , Disponibilidade Biológica , Densidade Óssea/efeitos dos fármacos , Reabsorção Óssea/tratamento farmacológico , Cães , Relação Dose-Resposta a Droga , Avaliação Pré-Clínica de Medicamentos/métodos , Feminino , Humanos , Concentração Inibidora 50 , Integrinas/metabolismo , Macaca mulatta , Modelos Moleculares , Naftiridinas/química , Naftiridinas/farmacocinética , Osteoporose/prevenção & controle , Ovariectomia , Ratos , Ratos Sprague-Dawley , Receptores de Vitronectina/metabolismo , Relação Estrutura-AtividadeRESUMO
OBJECTIVE: Develop a rat model for the evaluation of estrogenic agents on estrogen deficiency-induced changes in thermoregulation. METHODS: OVX rats are impaired in thermoregulation which manifests itself as an elevation in basal tail skin temperature (TST) and are less able to respond to temperature changes than intact rats. RESULTS: Administration of estrogen subcutaneously to estrogen-depleted rats either as depot formulation, biodegradable pellets, or daily injections, suppressed the increased TST. OVX rats maintained on a diet devoid of phytoestrogens had a higher TST by several degrees than OVX rats fed normal chow, offering greater ability to test estrogenic agents on thermoregulation. Depletion of estrogen in intact rats via chronic administration of leuprolide acetate, a GnRH agonist, also increased TST, which was in turn suppressed by estrogen. In intact rats, tamoxifen exhibited estrogen antagonistic activity elevating TST, while in OVX rats, tamoxifen acted as an agonist by suppressing TST. CONCLUSION: OVX rats kept on a diet devoid of phytoestrogens are a sensitive model for estrogen-dependent thermoregulation.
Assuntos
Estrogênios/farmacologia , Fitoestrógenos/farmacologia , Temperatura Cutânea/efeitos dos fármacos , Cauda/fisiologia , Tamoxifeno/farmacologia , Animais , Antagonistas de Estrogênios/farmacologia , Feminino , Modelos Animais , Ovariectomia , Ratos , Ratos Sprague-Dawley , Cauda/efeitos dos fármacos , Fatores de TempoRESUMO
A series of novel, highly potent alpha(v)beta(3) receptor antagonists with favorable pharmacokinetic profiles has been identified. In this series of antagonists, 2-aryl beta-amino acids function as potent aspartic acid replacements.
Assuntos
Aminoácidos/química , Ésteres/química , Receptores de Vitronectina/antagonistas & inibidores , Aminoácidos/síntese química , Aminoácidos/farmacocinética , Animais , Ácido Aspártico/química , Materiais Biomiméticos/síntese química , Materiais Biomiméticos/química , Materiais Biomiméticos/farmacocinética , Cães , Avaliação Pré-Clínica de Medicamentos , Ésteres/síntese química , Ésteres/farmacocinética , Humanos , Concentração Inibidora 50 , Oligopeptídeos/química , Oligopeptídeos/farmacocinética , Ligação Proteica , Receptores de Vitronectina/metabolismo , Relação Estrutura-AtividadeRESUMO
Mimetics of the RGD tripeptide are described that are potent, selective antagonists of the integrin receptor, alpha(v)beta(3). The use of the 5,6,7,8-tetrahydro[1,8]naphthyridine group as a potency-enhancing N-terminus is demonstrated. Two 3-substituted-3-amino-propionic acids previously contained in alpha(IIb)beta(3) antagonists were utilized to enhance binding affinity and functional activity for the targeted receptor. Further affinity increases were then achieved through the use of cyclic glycyl amide bond constraints.
Assuntos
Oligopeptídeos/farmacologia , Receptores de Vitronectina/antagonistas & inibidores , Amidas/síntese química , Amidas/química , Amidas/farmacologia , Ligação Competitiva , Desenho de Fármacos , Avaliação Pré-Clínica de Medicamentos , Humanos , Concentração Inibidora 50 , Conformação Molecular , Mimetismo Molecular , Oligopeptídeos/síntese química , Oligopeptídeos/química , Osteoporose/prevenção & controle , Agregação Plaquetária/efeitos dos fármacos , Receptores de Vitronectina/metabolismo , Relação Estrutura-AtividadeRESUMO
Potent non-peptidic alpha(v)beta(3) antagonists have been prepared incorporating various beta-amino acids as aspartic acid mimetics. Modification of the beta-alanine 3-substituents alters the potency and physicochemical properties of these receptor antagonists and in some cases provides orally bioavailable alpha(v)beta(3) inhibitors.