RESUMO
Using structure based drug design, novel aminobenzisoxazoles as coagulation factor IXa inhibitors were designed and synthesized. Highly selective inhibition of FIXa over FXa was demonstrated. Anticoagulation profile of selected compounds was evaluated by aPTT and PT tests. In vitro ADMET and pharmacokinetic (PK) profiles were also evaluated.
Assuntos
Fator IXa/antagonistas & inibidores , Isoxazóis/química , Animais , Sítios de Ligação , Coagulação Sanguínea/efeitos dos fármacos , Cristalografia por Raios X , Cães , Desenho de Fármacos , Avaliação Pré-Clínica de Medicamentos , Fator IXa/metabolismo , Meia-Vida , Humanos , Concentração Inibidora 50 , Isoxazóis/metabolismo , Isoxazóis/farmacologia , Simulação de Dinâmica Molecular , Tempo de Tromboplastina Parcial , Estrutura Terciária de Proteína , Tempo de Protrombina , Ratos , Relação Estrutura-AtividadeRESUMO
Using structure based drug design (SBDD), a novel class of potent coagulation Factor IXa (FIXa) inhibitors was designed and synthesized. High selectivity over FXa inhibition was achieved. Selected compounds demonstrated oral bioavailability in rat IV/PO pharmacokinetic (PK) studies. Finally, the pharmacodynamics (PD) of this class of molecules was evaluated in Thrombin Generation Assay (TGA) in Corn Trypsin Inhibitor (CTI) citrated human plasma and demonstrated characteristics of a FIXa inhibitor.
Assuntos
Aminas/farmacologia , Inibidores Enzimáticos/farmacologia , Fator IXa/antagonistas & inibidores , Administração Oral , Aminas/síntese química , Aminas/química , Animais , Disponibilidade Biológica , Cristalografia por Raios X , Relação Dose-Resposta a Droga , Desenho de Fármacos , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Fator IXa/metabolismo , Humanos , Modelos Moleculares , Estrutura Molecular , Ratos , Relação Estrutura-AtividadeRESUMO
Using structure based drug design, a novel class of potent coagulation factor IXa (FIXa) inhibitors was designed and synthesized. High selectivity over FXa inhibition was achieved. Selected compounds were evaluated in rat IV/PO pharmacokinetic (PK) studies and demonstrated desirable oral PK profiles. Finally, the pharmacodynamics (PD) of this class of molecules were evaluated in thrombin generation assay (TGA) in Corn Trypsin Inhibitor (CTI) citrated human plasma and demonstrated characteristics of a FIXa inhibitor.
Assuntos
Desenho de Fármacos , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/farmacologia , Fator IXa/antagonistas & inibidores , Compostos Heterocíclicos com 3 Anéis/química , Compostos Heterocíclicos com 3 Anéis/farmacologia , Administração Oral , Animais , Cristalografia por Raios X , Ativação Enzimática/efeitos dos fármacos , Inibidores Enzimáticos/química , Compostos Heterocíclicos com 3 Anéis/síntese química , Humanos , Estrutura Molecular , RatosRESUMO
We previously observed a cutaneous type IV immune response in nonhuman primates (NHP) with the mGlu5 negative allosteric modulator (NAM) 7. To determine if this adverse event was chemotype- or mechanism-based, we evaluated a distinct series of mGlu5 NAMs. Increasing the sp3 character of high-throughput screening hit 40 afforded a novel morpholinopyrimidone mGlu5 NAM series. Its prototype, (R)-6-neopentyl-2-(pyridin-2-ylmethoxy)-6,7-dihydropyrimido[2,1-c][1,4]oxazin-4(9H)-one (PF-06462894, 8), possessed favorable properties and a predicted low clinical dose (2 mg twice daily). Compound 8 did not show any evidence of immune activation in a mouse drug allergy model. Additionally, plasma samples from toxicology studies confirmed that 8 did not form any reactive metabolites. However, 8 caused the identical microscopic skin lesions in NHPs found with 7, albeit with lower severity. Holistically, this work supports the hypothesis that this unique toxicity may be mechanism-based although additional work is required to confirm this and determine clinical relevance.
Assuntos
Regulação Alostérica/efeitos dos fármacos , Compostos Heterocíclicos com 3 Anéis/farmacologia , Compostos Heterocíclicos com 3 Anéis/farmacocinética , Piridinas/farmacologia , Piridinas/farmacocinética , Receptor de Glutamato Metabotrópico 5/antagonistas & inibidores , Receptor de Glutamato Metabotrópico 5/metabolismo , Animais , Feminino , Células HEK293 , Compostos Heterocíclicos com 3 Anéis/efeitos adversos , Compostos Heterocíclicos com 3 Anéis/química , Humanos , Masculino , Simulação de Acoplamento Molecular , Piridinas/efeitos adversos , Piridinas/química , Ratos , Ratos Sprague-Dawley , Relação Estrutura-AtividadeRESUMO
A novel series of pyrazolopyrazines is herein disclosed as mGluR5 negative allosteric modulators (NAMs). Starting from a high-throughput screen (HTS) hit (1), a systematic structure-activity relationship (SAR) study was conducted with a specific focus on balancing pharmacological potency with physicochemical and pharmacokinetic (PK) properties. This effort led to the discovery of 1-methyl-3-(4-methylpyridin-3-yl)-6-(pyridin-2-ylmethoxy)-1H-pyrazolo[3,4-b]pyrazine (PF470, 14) as a highly potent, selective, and orally bioavailable mGluR5 NAM. Compound 14 demonstrated robust efficacy in a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-rendered Parkinsonian nonhuman primate model of l-DOPA-induced dyskinesia (PD-LID). However, the progression of 14 to the clinic was terminated because of a potentially mechanism-mediated finding consistent with a delayed-type immune-mediated type IV hypersensitivity in a 90-day NHP regulatory toxicology study.
Assuntos
Pirazinas/síntese química , Pirazóis/síntese química , Receptor de Glutamato Metabotrópico 5/metabolismo , 1-Metil-4-Fenil-1,2,3,6-Tetra-Hidropiridina , Administração Oral , Regulação Alostérica , Animais , Antiparkinsonianos/efeitos adversos , Disponibilidade Biológica , Permeabilidade da Membrana Celular , Cães , Discinesia Induzida por Medicamentos/tratamento farmacológico , Células HEK293 , Humanos , Hipersensibilidade Tardia/induzido quimicamente , Levodopa/efeitos adversos , Macaca fascicularis , Células Madin Darby de Rim Canino , Masculino , Microssomos Hepáticos/metabolismo , Modelos Moleculares , Doença de Parkinson/tratamento farmacológico , Doença de Parkinson/etiologia , Doença de Parkinson/fisiopatologia , Pirazinas/farmacologia , Pirazinas/toxicidade , Pirazóis/farmacologia , Pirazóis/toxicidade , Ensaio Radioligante , Ratos , Ratos Sprague-Dawley , Relação Estrutura-AtividadeRESUMO
Novel NR2B antagonists with an amide tether were found by an approach to avoid pharmacophoric similarity to dofetilide. Structure-activity relationship investigation led to N-[cis-4-hydroxy-4-(5-hydroxypyridin-2-yl)cyclohexyl]-3-henylpropanamide as an orally active NR2B-subtype selective N-methyl-D-aspartate (NMDA) receptor antagonist with very weak HERG (human ether-a-go-go related gene) binding (IC(50)> 30 microM). This compound exhibited potent in vivo anti-allodynic activity in the mouse partial sciatic nerve ligation (PSL) model (minimum effective dose=10 mg/kg, po).
Assuntos
Desenho de Fármacos , Canais de Potássio Éter-A-Go-Go/metabolismo , N-Metilaspartato/antagonistas & inibidores , N-Metilaspartato/metabolismo , Piridinas/química , Piridinas/farmacologia , Receptores de N-Metil-D-Aspartato/metabolismo , Administração Oral , Concentração Inibidora 50 , Estrutura Molecular , N-Metilaspartato/administração & dosagem , Piridinas/síntese química , Solubilidade , Relação Estrutura-AtividadeRESUMO
A novel potent NMDA-NR2B selective antagonist without the reactive metabolites formation issue was identified. Through this study, a close correlation between reactive metabolites formation and calculated HOMO energies of parent compounds was found.
Assuntos
Amidas/química , Amidas/farmacologia , Receptores de N-Metil-D-Aspartato/antagonistas & inibidores , Receptores de N-Metil-D-Aspartato/metabolismo , Amidas/síntese química , Amidas/metabolismo , Animais , Linhagem Celular , Glutationa/química , Humanos , Camundongos , Estrutura Molecular , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Fenol/química , Fenóis/química , Relação Estrutura-AtividadeRESUMO
(-)-6-[2-[4-(3-Fluorophenyl)-4-hydroxy-1-piperidinyl]-1-hydroxyethyl]-3,4-dihydro-2(1H)-quinolinone was identified as an orally active NR2B-subunit selective N-methyl-d-aspartate (NMDA) receptor antagonist. It has very high selectivity for NR2B subunits containing NMDA receptors versus the HERG-channel inhibition (therapeutic index=4200 vs NR2B binding IC(50)). This compound has improved pharmacokinetic properties compared to the prototype CP-101,606.