RESUMO
Parathyroid hormone (PTH) is essential for calcium homeostasis and its action is mediated by the PTH type 1 receptor (PTHR1), a class B G-protein-coupled receptor. Hypoparathyroidism and osteoporosis can be treated with PTH injections; however, no orally effective PTH analogue is available. Here we show that PCO371 is a novel, orally active small molecule that acts as a full agonist of PTHR1. PCO371 does not affect the PTH type 2 receptor (PTHR2), and analysis using PTHR1-PTHR2 chimeric receptors indicated that Proline 415 of PTHR1 is critical for PCO371-mediated PTHR1 activation. Oral administration of PCO371 to osteopenic rats provokes a significant increase in bone turnover with limited increase in bone mass. In hypocalcemic rats, PCO371 restores serum calcium levels without increasing urinary calcium, and with stronger and longer-lasting effects than PTH injections. These results strongly suggest that PCO371 can provide a new treatment option for PTH-related disorders, including hypoparathyroidism.
Assuntos
Hipoparatireoidismo/tratamento farmacológico , Imidazolidinas/síntese química , Receptor Tipo 1 de Hormônio Paratireóideo/agonistas , Compostos de Espiro/síntese química , Animais , Cães , Feminino , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Imidazolidinas/farmacologia , Masculino , Estrutura Molecular , Mutação , Glândulas Paratireoides/efeitos dos fármacos , Glândulas Paratireoides/cirurgia , Ratos , Compostos de Espiro/farmacologiaRESUMO
Selective factor VIIa-tissue factor complex (FVIIa/TF) inhibition is regarded as a promising target for developing new anticoagulant drugs. In previous reports, we described a S3 subsite found in the X-ray crystal structure of compound 2 that bound to FVIIa/soluble tissue factor (sTF). Based on the X-ray crystal structure information and with the aim of improving the inhibition activity for FVIIa/TF and selectivity against other serine proteases, we synthesized derivatives by introducing substituents at position 5 of the indole ring of compound 2. Among them, compound 16 showed high selectivity against other serine proteases. Contrary to our expectations, compound 16 did not occupy the S3-subsite; X-ray structure analysis revealed that compound 16 improved selectivity by forming hydrogen bonds with Gln217, Thr99 and Asn100.
Assuntos
Fator VIIa/antagonistas & inibidores , Fator VIIa/metabolismo , Peptídeos/química , Peptídeos/farmacologia , Biomimética , Cristalografia por Raios X , Fator VIIa/química , Modelos Moleculares , Ligação Proteica , Tromboplastina/antagonistas & inibidores , Tromboplastina/química , Tromboplastina/metabolismoRESUMO
Selective factor VIIa-tissue factor complex (FVIIa/TF) inhibition is regarded as a promising target for developing new anticoagulant drugs. Compound 1 was discovered from focused screening of serine protease-directed compounds from our internal collection. Using parallel synthesis supported by structure-based drug design, we identified peptidemimetic FVIIa/TF inhibitors (compounds 4-11) containing L-Gln or L-Met as the P2 moiety. However, these compounds lacked the selectivity of other serine proteases in the coagulation cascade, especially thrombin. Further optimization of these compounds was carried out with a focus on the P4 moiety. Among the optimized compounds, 12b-f showed improved selectivity.
Assuntos
Química Farmacêutica/métodos , Fator VIIa/antagonistas & inibidores , Serina Endopeptidases/farmacologia , Inibidores de Serina Proteinase/síntese química , Tromboembolia/tratamento farmacológico , Coagulação Sanguínea/efeitos dos fármacos , Cristalografia por Raios X/métodos , Desenho de Fármacos , Humanos , Cinética , Modelos Químicos , Conformação Molecular , Peptídeos/química , Serina Endopeptidases/química , Inibidores de Serina Proteinase/química , Tromboembolia/enzimologiaRESUMO
Side-chain elongation of active vitamin D3 is acknowledged as a structural modification to enhance its cell differentiation activity; however, the comprehensive structure-activity relationship (SAR) as a result of this modification has not been reported. To clarify the SAR, we synthesized six analogs systematically elongated at the 24-position, 26,27-position, or both by methylene (normal A-ring series 1a-f) in a facile parallel solution-phase synthesis. Using parallel synthesis, we expanded the side chain-elongation study into two 19-exomethylene analog series: 19-nor-A-ring (4a-f) and 2-methylene-19-nor-A-ring (5a-f). In the 19-nor-A-ring analog series, the SAR induced by side-chain elongation was similar to the normal A-ring analog series, but in the 2-methylene-19-nor-A-ring series, the SAR was unique.