RESUMO
A second-generation small molecule P2X3 receptor antagonist has been developed. The lead optimization strategy to address shortcomings of the first-generation preclinical lead compound is described herein. These studies were directed towards the identification and amelioration of preclinical hepatobiliary findings, reducing potential for drug-drug interactions, and decreasing the projected human dose of the first-generation lead.
Assuntos
Analgésicos/uso terapêutico , Benzamidas/uso terapêutico , Dor/tratamento farmacológico , Antagonistas do Receptor Purinérgico P2X/uso terapêutico , Piridinas/uso terapêutico , Receptores Purinérgicos P2X3/metabolismo , Analgésicos/síntese química , Analgésicos/química , Analgésicos/farmacocinética , Animais , Benzamidas/síntese química , Benzamidas/química , Benzamidas/farmacocinética , Cães , Desenho de Fármacos , Interações Medicamentosas , Glucuronosiltransferase/antagonistas & inibidores , Meia-Vida , Hiperbilirrubinemia/prevenção & controle , Estrutura Molecular , Antagonistas do Receptor Purinérgico P2X/síntese química , Antagonistas do Receptor Purinérgico P2X/química , Antagonistas do Receptor Purinérgico P2X/farmacocinética , Piridinas/síntese química , Piridinas/química , Piridinas/farmacocinética , Ratos , Estereoisomerismo , 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
A new class of CGRP receptor antagonists was identified by replacing the central amide of a previously identified anilide lead structure with ethylene, ethane, or ethyne linkers. (E)-Alkenes as well as alkynes were found to preserve the proper bioactive conformation of the amides, necessary for efficient receptor binding. Further exploration resulted in several potent compounds against CGRP-R with low susceptibility to P-gp mediated efflux.
Assuntos
Alcenos/farmacologia , Antagonistas do Receptor do Peptídeo Relacionado ao Gene de Calcitonina , Alcenos/síntese química , Alcenos/química , Amidas/química , Relação Dose-Resposta a Droga , Células HEK293 , Humanos , Estrutura Molecular , Relação Estrutura-AtividadeRESUMO
Calcitonin gene-related peptide (CGRP) is a potent neuropeptide whose agonist interaction with the CGRP receptor (CGRP-R) in the periphery promotes vasodilation, neurogenic inflammation and trigeminovascular sensory activation. This process is implicated in the cause of migraine headaches, and CGRP-R antagonists in clinical development have proven effective in treating migraine-related pain in humans. CGRP-R is expressed on blood vessel smooth muscle and sensory trigeminal neurons and fibers in the periphery as well as in the central nervous system. However, it is not clear what role the inhibition of central CGRP-R plays in migraine pain relief. To this end, the CGRP-R positron emission tomography (PET) tracer [(11)C]MK-4232 (2-[(8R)-8-(3,5-difluorophenyl)-6,8-[6-(11)C]dimethyl-10-oxo-6,9-diazaspiro[4.5]decan-9-yl]-N-[(2R)-2'-oxospiro[1,3-dihydroindene-2,3'-1H-pyrrolo[2,3-b]pyridine]-5-yl]acetamide) was discovered and developed for use in clinical PET studies. In rhesus monkeys and humans, [(11)C]MK-4232 displayed rapid brain uptake and a regional brain distribution consistent with the known distribution of CGRP-R. Monkey PET studies with [(11)C]MK-4232 after intravenous dosing with CGRP-R antagonists validated the ability of [(11)C]MK-4232 to detect changes in CGRP-R occupancy in proportion to drug plasma concentration. Application of [(11)C]MK-4232 in human PET studies revealed that telcagepant achieved only low receptor occupancy at an efficacious dose (140 mg PO). Therefore, it is unlikely that antagonism of central CGRP-R is required for migraine efficacy. However, it is not known whether high central CGRP-R antagonism may provide additional therapeutic benefit.
Assuntos
Acetanilidas/farmacocinética , Analgésicos/farmacocinética , Azepinas/farmacocinética , Encéfalo/metabolismo , Antagonistas do Receptor do Peptídeo Relacionado ao Gene de Calcitonina , Imidazóis/farmacocinética , Tomografia por Emissão de Pósitrons/métodos , Compostos Radiofarmacêuticos/farmacocinética , Compostos de Espiro/farmacocinética , Acetanilidas/química , Adulto , Analgésicos/uso terapêutico , Animais , Azepinas/uso terapêutico , Encéfalo/diagnóstico por imagem , Radioisótopos de Carbono , Feminino , Humanos , Imidazóis/uso terapêutico , Macaca mulatta , Masculino , Pessoa de Meia-Idade , Transtornos de Enxaqueca/tratamento farmacológico , Transtornos de Enxaqueca/metabolismo , Estrutura Molecular , Ligação Proteica , Compostos Radiofarmacêuticos/química , Especificidade da Espécie , Compostos de Espiro/química , Distribuição Tecidual , Adulto JovemRESUMO
The cerebellum is classically considered to be mainly involved in motor processing, but studies have suggested several other functions, including pain processing. Calcitonin-gene-related peptide (CGRP) is a neuropeptide involved in migraine pathology, where there is elevated release of CGRP during migraine attacks and CGRP receptor antagonists have antimigraine efficacy. In the present study, we examined CGRP and CGRP receptor binding sites and protein expression in primate cerebellar cortex. Additionally, mRNA expression of the CGRP receptor components, calcitonin receptor-like receptor (CLR) and receptor activity modifying protein 1 (RAMP1), was examined. In addition, expression of procalcitonin was studied. We observed high [(3)H]MK-3207 (CGRP receptor antagonist) binding densities in the molecular layer of rhesus cerebellar cortex; however, due to the limit of resolution of the autoradiographic image the exact cellular localization could not be determined. Similarly, [(125)I]CGRP binding was observed in the molecular layer and Purkinje cell layer of human cerebellum. CLR and RAMP1 mRNA was expressed within the Purkinje cell layer and some expression was found in the molecular layer. Immunofluorescence revealed expression of CGRP, CLR, and RAMP1 in the Purkinje cells and in cells in the molecular layer. Procalcitonin was found in the same localization. Recent research in the biology of cerebellum indicates that it may have a role in nociception. For the first time we have identified CGRP and CGRP receptor binding sites together with CGRP receptor expression through protein and mRNA localization in primate cerebellar cortex. These results point toward a functional role of CGRP in cerebellum. Further efforts are needed to evaluate this.
Assuntos
Sítios de Ligação/fisiologia , Peptídeo Relacionado com Gene de Calcitonina/metabolismo , Córtex Cerebelar/metabolismo , Receptores de Peptídeo Relacionado com o Gene de Calcitonina/metabolismo , Idoso , Idoso de 80 Anos ou mais , Animais , Peptídeo Relacionado com Gene de Calcitonina/genética , Córtex Cerebelar/anatomia & histologia , Feminino , Glutamato Descarboxilase/metabolismo , Humanos , Macaca mulatta , Masculino , Proteínas do Tecido Nervoso/metabolismo , Mudanças Depois da Morte , Ligação Proteica/fisiologia , Ensaio Radioligante , Receptores de Peptídeo Relacionado com o Gene de Calcitonina/genéticaRESUMO
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
Clinical and experimental results have revealed a fundamental role of calcitonin gene-related peptide (CGRP) in primary headaches. CGRP is widely expressed in neurons both in the central nervous system (CNS) and in peripheral sensory nerves. In the CNS there is a wide distribution of CGRP-containing neurons with the highest levels seen in striatum, amygdale and cerebellum. Moreover, in acute attacks of migraine there is evidence of cerebellar activation. To understand the role of CGRP, antibodies towards the CGRP receptor components calcitonin receptor-like receptor (CLR) and receptor activity modifying protein type 1 (RAMP1) have been developed. In the present study we therefore examined immunohistochemically the distribution of CGRP and its receptor components in the cerebellum. CGRP immunoreactivity was only found intracellularly in the cerebellar Purkinje cell bodies, whereas CLR and RAMP1 were detected on the surface of the Purkinje cell bodies and in their processes. The elaborate dendritic tree of Purkinje cell fibers was distinctly visualized with the RAMP1 antibody. In addition, profoundly stained fibers spanning from the molecular layer into the medulla was observed with the RAMP1 antibody. Judged from the high density of immunoreactive cells expressing CGRP, RAMP1 or CLR, and from the double staining of CGRP and RAMP1 it is likely that most, if not all, Purkinje cells express both the peptide and the receptor components. Double staining with RAMP1 and the glial cell markers glial fibrillary acidic protein (GFAP) and S-100 revealed an almost identical staining pattern of the antibodies in the area of the cell body surfaces. However, as judged by confocal microscopy, no double staining was present. Instead, it was discovered that the glial cells tightly surrounded the Purkinje cells which easily could be interpreted as co-localization in the epifluorescence microscope. Our observations demonstrate that there is a rich expression of CGRP and CGRP receptor elements in the cerebellum which points towards a functional role of CGRP in cerebellar Purkinje cells. Recent advances in the biology of the cerebellum indicate that there may be a role in nociception; hence a target of the recently discovered CGRP receptor antagonists that have demonstrated improvement in migraine pain and associated symptoms could be cerebellar CGRP receptors.
Assuntos
Peptídeo Relacionado com Gene de Calcitonina/metabolismo , Proteína Semelhante a Receptor de Calcitonina/metabolismo , Cerebelo/metabolismo , Proteína 1 Modificadora da Atividade de Receptores/metabolismo , Receptores de Peptídeo Relacionado com o Gene de Calcitonina/metabolismo , Animais , Peptídeo Relacionado com Gene de Calcitonina/genética , Proteína Semelhante a Receptor de Calcitonina/genética , Cerebelo/citologia , Humanos , Transtornos de Enxaqueca/fisiopatologia , Células de Purkinje/citologia , Células de Purkinje/metabolismo , Ratos , Proteína 1 Modificadora da Atividade de Receptores/genética , Receptores de Peptídeo Relacionado com o Gene de Calcitonina/genéticaRESUMO
Identification of an HIV integrase inhibitor with micromolar affinity for the CGRP receptor led to the discovery of a series of structurally novel CGRP receptor antagonists. Optimization of this series produced compound 16, a low-molecular weight CGRP receptor antagonist with good pharmacokinetic properties in both rat and dog. In contrast to other nonpeptide antagonists, the activity of 16 was affected by the presence of divalent cations and showed evidence of an alternative, RAMP-independent CGRP receptor binding site.
Assuntos
Antagonistas do Receptor do Peptídeo Relacionado ao Gene de Calcitonina , Inibidores de Integrase de HIV/química , Inibidores de Integrase de HIV/farmacologia , Piridinas/química , Piridinas/farmacologia , Proteínas Modificadoras da Atividade de Receptores/metabolismo , Receptores de Peptídeo Relacionado com o Gene de Calcitonina/metabolismo , Animais , Linhagem Celular , Cães , HIV/enzimologia , Inibidores de Integrase de HIV/farmacocinética , Humanos , Ligação Proteica , Piridinas/farmacocinética , RatosRESUMO
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
Calcitonin gene-related peptide (CGRP) has long been hypothesized to play a key role in migraine pathophysiology, and the advent of small-molecule antagonists has clearly demonstrated a clinical link between blocking the CGRP receptor and migraine efficacy. 2-[(8R)-8-(3,5-Difluorophenyl)-10-oxo-6,9-diazaspiro[4.5]dec-9-yl]-N-[(2R)-2'-oxo-1,1',2',3-tetrahydrospiro[indene-2,3'-pyrrolo[2,3-b]pyridin]-5-yl]acetamide (MK-3207) represents the third CGRP receptor antagonist to display clinical efficacy in migraine trials. Here, we report the pharmacological characterization of MK-3207, a potent and orally bioavailable CGRP receptor antagonist. In vitro, MK-3207 is a potent antagonist of the human and rhesus monkey CGRP receptors (K(i) = 0.024 nM). In common with other CGRP receptor antagonists, MK-3207 displays lower affinity for CGRP receptors from other species, including canine and rodent. As a consequence of species selectivity, the in vivo potency was assessed in a rhesus monkey pharmacodynamic assay measuring capsaicin-induced changes in forearm dermal blood flow via laser Doppler imaging. MK-3207 produced a concentration-dependent inhibition of dermal vasodilation, with plasma concentrations of 0.8 and 7 nM required to block 50 and 90% of the blood flow increase, respectively. The tritiated analog [3H]MK-3207 was used to study the binding characteristics on the human CGRP receptor. [3H]MK-3207 displayed reversible and saturable binding (K(D) = 0.06 nM), and the off-rate was determined to be 0.012 min(-1), with a t(1/2) value of 59 min. In vitro autoradiography studies on rhesus monkey brain slices identified the highest level of binding in the cerebellum, brainstem, and meninges. Finally, as an index of central nervous system penetrability, the in vivo cerebrospinal fluid/plasma ratio was determined to be 2 to 3% in cisterna magna-ported rhesus monkeys.
Assuntos
Compostos Bicíclicos Heterocíclicos com Pontes/farmacologia , Antagonistas do Receptor do Peptídeo Relacionado ao Gene de Calcitonina , Compostos de Espiro/farmacologia , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/metabolismo , Animais , Autorradiografia , Ligação Competitiva , Transporte Biológico , Encéfalo/metabolismo , Compostos Bicíclicos Heterocíclicos com Pontes/sangue , Compostos Bicíclicos Heterocíclicos com Pontes/líquido cefalorraquidiano , Linhagem Celular , Chlorocebus aethiops , Feminino , Humanos , Cinética , Macaca mulatta , Masculino , Camundongos , Ensaio Radioligante , Receptores de Adrenomedulina , Receptores da Calcitonina/metabolismo , Receptores de Peptídeo Relacionado com o Gene de Calcitonina/fisiologia , Receptores de Polipeptídeo Amiloide de Ilhotas Pancreáticas , Receptores de Peptídeos/metabolismo , Compostos de Espiro/sangue , Compostos de Espiro/líquido cefalorraquidiano , Vasodilatação/efeitos dos fármacosRESUMO
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 class of CGRP receptor antagonists was rationally designed by modifying a highly potent, but structurally complex, CGRP receptor antagonist. Initial modifications focused on simplified structures, with increased flexibility. Subsequent to the preparation of a less-potent but more flexible lead, classic medicinal chemistry methods were applied to restore high affinity (compound 22, CGRP Ki=0.035 nM) while maintaining structural diversity relative to the lead. Good selectivity against the closely related adrenomedullin-2 receptor was also achieved.
Assuntos
Acetamidas/química , Antagonistas do Receptor do Peptídeo Relacionado ao Gene de Calcitonina , Compostos de Espiro/química , Acetamidas/síntese química , Acetamidas/farmacologia , Animais , Linhagem Celular , Desenho de Fármacos , Humanos , Ratos , Receptores de Peptídeo Relacionado com o Gene de Calcitonina/metabolismo , Compostos de Espiro/síntese química , Compostos de Espiro/farmacologia , 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.
Assuntos
Antagonistas do Receptor do Peptídeo Relacionado ao Gene de Calcitonina , Indóis/síntese química , Compostos de Espiro/síntese química , Administração Oral , Animais , Disponibilidade Biológica , Cães , Descoberta de Drogas , Humanos , Indóis/farmacologia , Macaca mulatta , Oxindóis , Compostos de Espiro/farmacologia , Relação Estrutura-AtividadeRESUMO
A series of tricyclic CGRP receptor antagonists was optimized in order to improve oral bioavailability. Attenuation of polar surface area and incorporation of a weakly basic indoline nitrogen led to compound 5, a potent antagonist with good oral bioavailability in three species.
Assuntos
Antagonistas do Receptor do Peptídeo Relacionado ao Gene de Calcitonina , Compostos Heterocíclicos com 3 Anéis/farmacocinética , Compostos de Espiro/farmacocinética , Administração Oral , Animais , Disponibilidade Biológica , Linhagem Celular , Cães , Haplorrinos , Compostos Heterocíclicos com 3 Anéis/administração & dosagem , Compostos Heterocíclicos com 3 Anéis/química , Humanos , Ratos , Receptores de Peptídeo Relacionado com o Gene de Calcitonina/metabolismo , Compostos de Espiro/administração & dosagemRESUMO
Calcitonin gene-related peptide (CGRP) is a potent neuropeptide that plays a key role in the pathophysiology of migraine headache. CGRP levels in the cranial circulation are increased during a migraine attack, and CGRP itself has been shown to trigger migraine-like headache. The correlation between CGRP release and migraine headache points to the potential utility of CGRP receptor antagonists as novel therapeutics in the treatment of migraine. Indeed, clinical proof-of-concept in the acute treatment of migraine was demonstrated with an intravenous formulation of the CGRP receptor antagonist BIBN4096BS (olcegepant). Here we report on the pharmacological characterization of the first orally bioavailable CGRP receptor antagonist in clinical development, MK-0974 [N-[(3R,6S)-6-(2,3-difluorophenyl)-2-oxo-1-(2,2,2-trifluoroethyl)azepan-3-yl]-4-(2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-1-yl)piperidine-1-carboxamide]. In vitro, MK-0974 is a potent antagonist of the human (K(i) = 0.77 nM) and rhesus (K(i) = 1.2 nM) CGRP receptors but displays >1500-fold lower affinity for the canine and rat receptors as determined via (125)I-human CGRP competition binding assays. A rhesus pharmacodynamic assay measuring capsaicin-induced changes in forearm dermal blood flow via laser Doppler imaging was utilized to determine the in vivo activity of CGRP receptor antagonism. MK-0974 produced a concentration-dependent inhibition of dermal vasodilation, generated by capsaicin-induced release of endogenous CGRP, with plasma concentrations of 127 and 994 nM required to block 50 and 90% of the blood flow increase, respectively. In conclusion, MK-0974 is a highly potent, selective, and orally bioavailable CGRP receptor antagonist, which may be valuable in the acute treatment of migraine.
Assuntos
Azepinas/administração & dosagem , Azepinas/química , Antagonistas do Receptor do Peptídeo Relacionado ao Gene de Calcitonina , Imidazóis/administração & dosagem , Imidazóis/química , Transtornos de Enxaqueca/tratamento farmacológico , Administração Oral , Animais , Linhagem Celular , Cães , Relação Dose-Resposta a Droga , Feminino , Humanos , Macaca mulatta , Masculino , Transtornos de Enxaqueca/metabolismo , Ligação Proteica/efeitos dos fármacos , Ligação Proteica/fisiologia , Ratos , Receptores de Peptídeo Relacionado com o Gene de Calcitonina/metabolismoRESUMO
In our effort to find potent, orally bioavailable CGRP receptor antagonists for the treatment of migraine, a novel series based on a pyridinone template was investigated. After optimizing the privileged structure and the placement of the attached phenyl ring, systematic SAR was carried out on both the N-alkyl and C-5 aryl substituents. Several analogs with good potency and pharmacokinetic profiles were identified.
Assuntos
Antagonistas do Receptor do Peptídeo Relacionado ao Gene de Calcitonina , Piridonas/farmacologia , Administração Oral , Animais , Disponibilidade Biológica , Meia-Vida , Piridonas/administração & dosagem , Piridonas/química , Piridonas/farmacocinética , Ratos , Relação Estrutura-AtividadeRESUMO
The previously disclosed spirohydantoin-based CGRP receptor antagonists were optimized for potency through modification of the benzimidazolone substituents. Compounds were identified which had minimal shift in the cAMP functional assay containing 50% human serum. Blockade of CGRP-mediated vasodilation was observed with these compounds in a rhesus pharmacodynamic assay and the in vivo potency correlated with the in vitro activity in the serum-shifted functional assay.
Assuntos
Benzimidazóis/síntese química , Benzimidazóis/farmacologia , Antagonistas do Receptor do Peptídeo Relacionado ao Gene de Calcitonina , Indanos/química , Compostos de Espiro/síntese química , Compostos de Espiro/farmacologia , Animais , Benzimidazóis/sangue , Benzimidazóis/química , Técnicas de Química Combinatória , Humanos , Macaca mulatta , Estrutura Molecular , Compostos de Espiro/química , Relação Estrutura-AtividadeRESUMO
Calcitonin gene-related peptide (CGRP) has been implicated in the pathogenesis of migraine. Herein we describe optimization of CGRP receptor antagonists based on an earlier lead structure containing a (3R)-amino-(6S)-phenylcaprolactam core. Replacement of the phenylimidazolinone with an azabenzimidazolone gave stable derivatives with lowered serum shifts. Extensive SAR studies of the C-6 aryl moiety revealed the potency-enhancing effect of the 2,3-difluorophenyl group, and trifluoroethylation of the N-1 amide position resulted in improved oral bioavailabilities, ultimately leading to clinical candidate 38 (MK-0974).