RESUMO
Single crystal X-ray diffraction (SCXRD), powder X-ray diffraction (PXRD), and solid-state NMR (SSNMR) techniques are used to analyze the structures of two nonsolvated polymorphs of {4-(4-chloro-3-fluorophenyl)-2-[4-(methyloxy)phenyl]-1,3-thiazol-5-yl} acetic acid. These polymorphs are enantiotropically-related with a thermodynamic transition temperature of 35 +/- 3 degrees C. The crystal structure of Form 1, which is thermodynamically more stable at lower temperatures, was determined by SCXRD. The crystal structure of Form 2 was determined using PXRD structure solution methods that were assisted using two types of SSNMR experiments, dipolar connectivity experiments and chemical shift measurements. These experiments determined certain aspects of local conformation and intermolecular packing in Form 2 in comparison to Form 1, and provided qualitative knowledge that assisted in obtaining the best possible powder structure solution from the X-ray data. NMR chemical shifts for 1H, 13C, 15N, and 19F nuclei in Forms 1 and 2 are sensitive to hydrogen-bonding behavior, molecular conformation, and aromatic pi-stacking interactions. Density functional theory (DFT) geometry optimizations were used in tandem with Rietveld refinement and NMR chemical shielding calculations to improve and verify the Form 2 structure. The energy balance of the system and other properties relevant to drug development are predicted and discussed.
Assuntos
Acetatos/química , Espectroscopia de Ressonância Magnética/métodos , Tiazóis/química , Cristalografia por Raios X , Ligação de Hidrogênio , Estrutura Molecular , EstereoisomerismoRESUMO
Starting from a potent ketone-based inhibitor with poor drug properties, incorporation of P(2)-P(3) elements from a ketoamide-based inhibitor led to the identification of a hybrid series of ketone-based cathepsin K inhibitors with better oral bioavailability than the starting ketone.
Assuntos
Catepsinas/antagonistas & inibidores , Inibidores de Cisteína Proteinase/química , Inibidores de Cisteína Proteinase/farmacocinética , Cetonas/química , Cetonas/farmacocinética , Administração Oral , Disponibilidade Biológica , Catepsina K , Catepsinas/química , Cristalografia por Raios X , Inibidores de Cisteína Proteinase/administração & dosagem , Humanos , Cetonas/administração & dosagem , Conformação Proteica , Relação Estrutura-AtividadeRESUMO
Starting from a potent pantolactone ketoamide cathepsin K inhibitor discovered from structural screening, conversion of the lactone scaffold to a pyrrolidine scaffold allowed exploration of the S(3) subsite of cathepsin K. Manipulation of P3 and P1' groups afforded potent inhibitors with drug-like properties.
Assuntos
Amidas , Catepsinas/antagonistas & inibidores , Inibidores de Cisteína Proteinase , Cetonas , Pirrolidinas , Amidas/síntese química , Amidas/farmacocinética , Amidas/farmacologia , Sítios de Ligação , Catepsina K , Catepsinas/química , Cristalografia por Raios X , Inibidores de Cisteína Proteinase/síntese química , Inibidores de Cisteína Proteinase/farmacocinética , Inibidores de Cisteína Proteinase/farmacologia , Humanos , Concentração Inibidora 50 , Cetonas/síntese química , Cetonas/farmacocinética , Cetonas/farmacologia , Modelos Moleculares , Estrutura Molecular , Pirrolidinas/síntese química , Pirrolidinas/farmacocinética , Pirrolidinas/farmacologia , Inibidores de Serina Proteinase , Relação Estrutura-AtividadeRESUMO
Starting from potent aldehyde inhibitors with poor drug properties, derivatization to semicarbazones led to the identification of a series of semicarbazone-based cathepsin K inhibitors with greater solubility and better pharmacokinetic profiles than their parent aldehydes. Furthermore, a representative semicarbazone inhibitor attenuated bone resorption in an ex vivo rat calvarial bone resorption model. However, based on enzyme inhibition comparisons at neutral pH, semicarbazone hydrolysis rates, and 13C NMR experiments, these semicarbazones probably function as prodrugs of aldehydes.
Assuntos
Aldeídos/química , Catepsinas/antagonistas & inibidores , Inibidores Enzimáticos/farmacologia , Semicarbazonas/farmacologia , Animais , Catepsina K , Cristalografia por Raios X , Avaliação Pré-Clínica de Medicamentos , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Humanos , Concentração de Íons de Hidrogênio , Hidrólise , Modelos Moleculares , Conformação Molecular , Pró-Fármacos/síntese química , Pró-Fármacos/química , Pró-Fármacos/farmacologia , Ratos , Semicarbazonas/síntese química , Semicarbazonas/química , Solubilidade , Relação Estrutura-AtividadeRESUMO
An orally bioavailable series of ketoamide-based cathepsin K inhibitors with good pharmacokinetic properties has been identified. Starting from a potent inhibitor endowed with poor drug properties, conformational constraint of the P(2)-P(3) linker and modifications to P(1') elements led to an enhancement in potency, solubility, clearance, and bioavailability. These optimized inhibitors attenuated bone resorption in a rat TPTX hypocalcemic bone resorption model.
Assuntos
Amidas/síntese química , Catepsinas/antagonistas & inibidores , Inibidores de Cisteína Proteinase/síntese química , Cetonas/síntese química , Amidas/farmacocinética , Amidas/farmacologia , Animais , Sítios de Ligação , Disponibilidade Biológica , Reabsorção Óssea/tratamento farmacológico , Reabsorção Óssea/metabolismo , Catepsina K , Catepsinas/química , Inibidores de Cisteína Proteinase/farmacocinética , Inibidores de Cisteína Proteinase/farmacologia , Modelos Animais de Doenças , Hipocalcemia/tratamento farmacológico , Hipocalcemia/metabolismo , Cetonas/farmacocinética , Cetonas/farmacologia , Ratos , Ratos Wistar , Solubilidade , Relação Estrutura-AtividadeRESUMO
Several novel ketoamide-based inhibitors of cathepsin K have been identified. Starting from a modestly potent inhibitor, structural screening of P2 elements led to 100-fold enhancements in inhibitory activity. Modifications to one of these leads resulted in an orally bioavailable cathepsin K inhibitor.
Assuntos
Amidas/farmacologia , Catepsinas/antagonistas & inibidores , Inibidores Enzimáticos/farmacologia , Amidas/síntese química , Amidas/farmacocinética , Sítios de Ligação , Disponibilidade Biológica , Catepsina K , Catepsinas/química , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/farmacocinética , Humanos , Cinética , Conformação Proteica , Proteínas Recombinantes/antagonistas & inibidores , Proteínas Recombinantes/química , Relação Estrutura-AtividadeRESUMO
A series of ketoamides were synthesized and evaluated for inhibitory activity against cathepsin K. Exploration of the interactions between achiral P(2) substituents and the cysteine protease based on molecular modelling suggestions resulted in potent cathepsin K inhibitors that demonstrated high selectivity versus cathepsins B, H, and L. Subsequent modifications of the P(3), P(1), and P(1') moieties afforded orally bioavailable inhibitors.
Assuntos
Amidas/síntese química , Catepsinas/antagonistas & inibidores , Inibidores de Cisteína Proteinase/síntese química , Amidas/farmacocinética , Amidas/farmacologia , Sítios de Ligação , Catepsina K , Catepsinas/química , Humanos , Relação Estrutura-AtividadeRESUMO
An orally available series of ketoamide-based inhibitors of cathepsin K has been identified. Starting from a potent inhibitor with poor oral bioavailability, modifications to P1 and P1' elements led to enhancements in solubility and permeability. These improvements resulted in orally available cathepsin K inhibitors.
Assuntos
Amidas/síntese química , Amidas/farmacologia , Catepsinas/antagonistas & inibidores , Administração Oral , Amidas/administração & dosagem , Animais , Disponibilidade Biológica , Catepsina K , Linhagem Celular , Cães , Humanos , Interações Hidrofóbicas e Hidrofílicas , Concentração Inibidora 50 , Farmacocinética , Relação Estrutura-AtividadeRESUMO
Osteoclast-mediated bone matrix resorption has been attributed to cathepsin K, a cysteine protease of the papain family that is abundantly and selectively expressed in osteoclast. Inhibition of cathepsin K could potentially be an effective method to prevent osteoporosis. Structure-activity studies on a series of reversible ketoamides based inhibitors of cathepsin K have led to identification of potent and selective compounds. Crystallographic studies have given insights into the mode of binding of these inhibitors. A series of ketoamides with varying P1 moieties were first synthesized to find an optimum group that would fit into the S1 subsite of the cysteine protease, cathepsin K. With a desired P1 group in place a variety of heterocyclic analogues in the P' region were synthesized to study their steric and electronic effects. In the process of exploring these P' heterocyclic variations, excellent selectivity was gained over other highly homologous cysteine proteases, including cathepsins L, S, and V. The favorable pharmacokinetic properties of some of these cathepsin K inhibitors in rats make them suitable for evaluation in rodent osteoporosis models. A representative cathepsin K inhibitor was shown to attenuate PTH-stimulated hypercalcemia in the TPTX rat model. These inhibitors provide a viable lead series in the discovery of new therapies for the prevention and treatment of osteoporosis
Assuntos
Amidas/síntese química , Catepsinas/antagonistas & inibidores , Inibidores de Cisteína Proteinase/síntese química , Cetonas/síntese química , Administração Oral , Amidas/farmacocinética , Amidas/farmacologia , Animais , Disponibilidade Biológica , Cálcio/sangue , Catepsina K , Catepsinas/química , Cristalografia por Raios X , Inibidores de Cisteína Proteinase/farmacocinética , Inibidores de Cisteína Proteinase/farmacologia , Humanos , Cetonas/farmacocinética , Cetonas/farmacologia , Masculino , Modelos Moleculares , Estrutura Molecular , Osteoporose/metabolismo , Ratos , Ratos Wistar , Proteínas Recombinantes/antagonistas & inibidores , Proteínas Recombinantes/química , Relação Estrutura-AtividadeRESUMO
A novel series of ketoamide-based inhibitors of cathepsin K has been identified. Modifications to P(2) and P(3) elements were crucial to enhancing inhibitory activity. Although not optimized, a selected inhibitor was effective in attenuating type I collagen hydrolysis in a surrogate assay of bone resorption.