RESUMO
A novel series of 3-amino-piperidin-2-one-based calcitonin gene-related peptide (CGRP) receptor antagonists was invented based upon the discovery of unexpected structure-activity observations. Initial exploration of the structure-activity relationships enabled the generation of a moderately potent lead structure (4). A series of modifications, including ring contraction and inversion of stereocenters, led to surprising improvements in CGRP receptor affinity. These studies identified compound 23, a structurally novel potent, orally bioavailable CGRP receptor antagonist.
Assuntos
Antagonistas do Receptor do Peptídeo Relacionado ao Gene de Calcitonina , Piperidinas , Antagonistas do Receptor do Peptídeo Relacionado ao Gene de Calcitonina/farmacologia , Antagonistas do Receptor do Peptídeo Relacionado ao Gene de Calcitonina/química , Antagonistas do Receptor do Peptídeo Relacionado ao Gene de Calcitonina/síntese química , Relação Estrutura-Atividade , Humanos , Piperidinas/química , Piperidinas/farmacologia , Piperidinas/síntese química , Animais , Ratos , Receptores de Peptídeo Relacionado com o Gene de Calcitonina/metabolismo , Estrutura MolecularRESUMO
High-throughput screening methods have been used to identify two novel series of inhibitors that disrupt progranulin binding to sortilin. Exploration of structure-activity relationships (SAR) resulted in compounds with sufficient potency and physicochemical properties to enable co-crystallization with sortilin. These co-crystal structures supported observed SAR trends and provided guidance for additional avenues for designing compounds with additional interactions within the binding site.
Assuntos
Proteínas Adaptadoras de Transporte Vesicular/metabolismo , Progranulinas/metabolismo , Bibliotecas de Moléculas Pequenas/química , Proteínas Adaptadoras de Transporte Vesicular/antagonistas & inibidores , Amidas/química , Amidas/metabolismo , Aminoácidos/química , Aminoácidos/metabolismo , Sítios de Ligação , Cristalografia por Raios X , Ensaios de Triagem em Larga Escala , Humanos , Simulação de Dinâmica Molecular , Progranulinas/antagonistas & inibidores , Ligação Proteica , Pirazóis/química , Pirazóis/metabolismo , Bibliotecas de Moléculas Pequenas/metabolismo , Relação Estrutura-AtividadeRESUMO
In our efforts to develop CGRP receptor antagonists as backups to MK-3207, 2, we employed a scaffold hopping approach to identify a series of novel oxazolidinone-based compounds. The development of a structurally diverse, potent (20, cAMP+HS IC50=0.67 nM), and selective compound (hERG IC50=19 µM) with favorable rodent pharmacokinetics (F=100%, t1/2=7h) is described. Key to this development was identification of a 3-substituted spirotetrahydropyran ring that afforded a substantial gain in potency (10 to 35-fold).
Assuntos
Antagonistas do Receptor do Peptídeo Relacionado ao Gene de Calcitonina , Transtornos de Enxaqueca/tratamento farmacológico , Oxazolidinonas/farmacologia , Oxazolidinonas/uso terapêutico , Animais , Relação Dose-Resposta a Droga , Humanos , Simulação de Acoplamento Molecular , Estrutura Molecular , Oxazolidinonas/síntese química , Oxazolidinonas/química , Ratos , Relação Estrutura-AtividadeRESUMO
Rational modification of the clinically tested CGRP receptor antagonist MK-3207 (3) afforded an analogue with increased unbound fraction in rat plasma and enhanced aqueous solubility, 2-[(8R)-8-(3,5-difluorophenyl)-8-methyl-10-oxo-6,9-diazaspiro[4.5]dec-9-yl]-N-[(6S)-2'-oxo-1',2',5,7-tetrahydrospiro[cyclopenta[b]pyridine-6,3'-pyrrolo[2,3-b]pyridin]-3-yl]acetamide (MK-8825) (6). Compound 6 maintained similar affinity to 3 at the human and rat CGRP receptors but possessed significantly improved in vivo potency in a rat pharmacodynamic model. The overall profile of 6 indicates it should find utility as a rat tool to investigate effects of CGRP receptor blockade in vivo.
Assuntos
Analgésicos/síntese química , Analgésicos/farmacologia , Antagonistas do Receptor do Peptídeo Relacionado ao Gene de Calcitonina , Transtornos de Enxaqueca/tratamento farmacológico , Piridinas/síntese química , Piridinas/farmacologia , Compostos de Espiro/síntese química , Compostos de Espiro/farmacologia , Administração Oral , Analgésicos/sangue , Animais , Disponibilidade Biológica , Modelos Animais de Doenças , Cães , Humanos , Macaca mulatta , Camundongos , Piridinas/sangue , Ratos , Receptores de Peptídeo Relacionado com o Gene de Calcitonina/metabolismo , Especificidade da Espécie , Compostos de Espiro/sangueRESUMO
In our ongoing efforts to develop CGRP receptor antagonists for the treatment of migraine, we aimed to improve upon telecagepant by targeting a compound with a lower projected clinical dose. Imidazoazepanes were identified as potent caprolactam replacements and SAR of the imidazole yielded the tertiary methyl ether as an optimal substituent for potency and hERG selectivity. Combination with the azabenzoxazinone spiropiperidine ultimately led to preclinical candidate 30 (MK-2918).
Assuntos
Azepinas/síntese química , Antagonistas do Receptor do Peptídeo Relacionado ao Gene de Calcitonina , Imidazóis/síntese química , Imidazóis/farmacologia , Analgésicos não Narcóticos/síntese química , Analgésicos não Narcóticos/química , Analgésicos não Narcóticos/farmacologia , Animais , Azepinas/química , Azepinas/farmacologia , Disponibilidade Biológica , Caprolactama/química , Células Cultivadas , Cães , Humanos , Imidazóis/química , Concentração Inibidora 50 , Macaca mulatta , Transtornos de Enxaqueca/tratamento farmacológico , Estrutura Molecular , Ratos , Relação Estrutura-AtividadeRESUMO
A previously utilized quinoline-for-N-phenylamide replacement strategy was employed against a central amide in a novel class of CGRP receptor antagonists. A unique and unexpected substitution pattern was ultimately required to maintain reasonable affinity for the CGRP receptor, while at the same time predicting acceptable heterocycle positioning for related analogs. Subsequently, specific quinoline and naphthyridine compounds were prepared which supported these structural predictions by displaying CGRP binding affinities in the 0.037-0.15 nM range.
Assuntos
Amidas/farmacologia , Antagonistas do Receptor do Peptídeo Relacionado ao Gene de Calcitonina , Amidas/química , EstereoisomerismoRESUMO
A novel series of potent CGRP receptor antagonists containing a central quinoline ring constraint was identified. The combination of the quinoline constraint with a tricyclic benzimidazolinone left hand fragment produced an analog with picomolar potency (14, CGRP K(i)=23 pM). Further optimization of the tricycle produced a CGRP receptor antagonist that exhibited subnanomolar potency (19, CGRP K(i)=0.52 nM) and displayed a good pharmacokinetic profile in three preclinical species.
Assuntos
Antagonistas do Receptor do Peptídeo Relacionado ao Gene de Calcitonina , Quinolinas/farmacologia , Animais , Disponibilidade Biológica , Cães , Avaliação Pré-Clínica de Medicamentos , Macaca mulatta , Quinolinas/química , Quinolinas/farmacocinética , RatosRESUMO
Several novel spiropiperidine-based CGRP receptor antagonists have been developed that maintain good potency and have reduced potential for metabolism.
Assuntos
Antagonistas do Receptor do Peptídeo Relacionado ao Gene de Calcitonina , Peptídeo Relacionado com Gene de Calcitonina/farmacologia , Fragmentos de Peptídeos/farmacologia , Piperidinas/farmacologia , Compostos de Espiro/farmacologia , Sequência de Aminoácidos , Animais , Peptídeo Relacionado com Gene de Calcitonina/química , Dicroísmo Circular , Clonagem Molecular , Humanos , Dados de Sequência Molecular , Fragmentos de Peptídeos/química , Piperidinas/química , Ligação Proteica , Transdução de Sinais , Compostos de Espiro/química , Relação Estrutura-AtividadeRESUMO
A novel series of annulated tricyclic compounds was synthesized and evaluated as NMDA/NR2B antagonists. Structure-activity development was directed towards in vitro optimization of NR2B activity and selectivity over the hERG K(+) channel. Preferred compounds were subsequently evaluated for selectivity in an alpha(1)-adrenergic receptor binding counter-screen and a cell-based assay of NR2B activity.
Assuntos
Benzocicloeptenos/síntese química , Neurotransmissores/síntese química , Piridinas/síntese química , Receptores de N-Metil-D-Aspartato/antagonistas & inibidores , Benzocicloeptenos/química , Benzocicloeptenos/farmacologia , Linhagem Celular , Canais de Potássio Éter-A-Go-Go/metabolismo , Humanos , Neurotransmissores/química , Neurotransmissores/farmacologia , Piridinas/química , Piridinas/farmacologia , Receptores de N-Metil-D-Aspartato/metabolismo , Relação Estrutura-AtividadeRESUMO
Rational modification of a previously identified spirohydantoin lead structure has identified a series of potent spiroazaoxindole CGRP receptor antagonists. The azaoxindole was found to be a general replacement for the hydantoin that consistently improved in vitro potency. The combination of the indanylspiroazaoxindole and optimized benzimidazolinones led to highly potent antagonists (e.g., 25, CGRP K(i)=40pM). The closely related compound 27 demonstrated good oral bioavailability in dog and rhesus.