RESUMO
Familial Parkinson's disease cases have recently been associated with the leucine rich repeat kinase 2 (LRRK2) gene. It has been hypothesized that inhibition of the LRRK2 protein may have the potential to alter disease pathogenesis. A dihydrobenzothiophene series of potent, selective, orally bioavailable LRRK2 inhibitors were identified from a high-throughput screen of the internal Merck sample collection. Initial SAR studies around the core established the series as a tractable small molecule lead series of LRRK2 inhibitors for potential treatment of Parkinson's disease. It was also found that incorporation of a lactam into the core drastically improved the CNS and DMPK properties of these small molecules.
Assuntos
Serina-Treonina Proteína Quinase-2 com Repetições Ricas em Leucina/antagonistas & inibidores , Inibidores de Proteínas Quinases/farmacologia , Tiofenos/farmacologia , Administração Oral , Disponibilidade Biológica , Relação Dose-Resposta a Droga , Humanos , Serina-Treonina Proteína Quinase-2 com Repetições Ricas em Leucina/metabolismo , Simulação de Acoplamento Molecular , Estrutura Molecular , Inibidores de Proteínas Quinases/administração & dosagem , Inibidores de Proteínas Quinases/química , Relação Estrutura-Atividade , Tiofenos/síntese química , Tiofenos/químicaRESUMO
SAR study of the piperidine moiety in a series of quinolizidinone carboxylic acid M(1) positive allosteric modulators was examined. While the SAR was generally flat, compounds were identified with high CNS exposure to warrant additional in vivo evaluation.
Assuntos
Piperidinas/farmacologia , Regulação Alostérica , Animais , Células CHO , Cricetinae , Cricetulus , Relação Dose-Resposta a Droga , Piperidinas/metabolismo , Relação Estrutura-AtividadeRESUMO
A series of benzothiophene methyl amines were examined in an effort to identify non-amidine chemotypes with reduced polypharmacology from existing leads with the goal of finding potent ASIC3 channel blockers to advance the therapeutic evaluation of ASIC3 inhibition.
Assuntos
Proteínas do Tecido Nervoso/antagonistas & inibidores , Bloqueadores dos Canais de Sódio/química , Canais Iônicos Sensíveis a Ácido , Amidinas/química , Amilorida/química , Animais , Proteínas do Tecido Nervoso/metabolismo , Ratos , Bloqueadores dos Canais de Sódio/farmacologia , Canais de Sódio/metabolismo , Relação Estrutura-AtividadeRESUMO
The phenyl ring in a series of quinolone carboxylic acid M(1) positive allosteric modulators was replaced with a variety of heterocycles in order to reduce protein plasma binding and enhance CNS exposure.
Assuntos
Ácidos Carboxílicos/farmacologia , Compostos Heterocíclicos/farmacologia , Piridonas/química , Regulação Alostérica , Animais , Proteínas Sanguíneas/química , Ácidos Carboxílicos/química , Ácidos Carboxílicos/farmacocinética , Compostos Heterocíclicos/química , Compostos Heterocíclicos/farmacocinética , Humanos , RatosRESUMO
A series of amiloride derivatives modified at the 5-position of the pyrazine ring were evaluated as inhibitors of acid-sensing ion channel-3 (ASIC3), a novel target for the treatment of chronic pain.
Assuntos
Amilorida/análogos & derivados , Química Farmacêutica/métodos , Proteínas do Tecido Nervoso/química , Dor/tratamento farmacológico , Canais de Sódio/química , Canais Iônicos Sensíveis a Ácido , Acidose , Amilorida/química , Aminas/química , Animais , Desenho de Fármacos , Eletrofisiologia , Concentração Inibidora 50 , Masculino , Modelos Químicos , Pirazinas/química , Ratos , Ratos Sprague-DawleyRESUMO
A series of indole amidines modified at the 2-position of the indole ring were evaluated as inhibitors of Acid-Sensing Ion Channel-3 (ASIC3), a novel target for the treatment of chronic pain.
Assuntos
Amidinas/química , Química Farmacêutica/métodos , Canais de Sódio/química , Canais Iônicos Sensíveis a Ácido , Animais , Desenho de Fármacos , Eletrofisiologia , Indóis/química , Concentração Inibidora 50 , Canais Iônicos/química , Masculino , Modelos Químicos , Naproxeno/farmacologia , Ratos , Ratos Sprague-Dawley , Relação Estrutura-AtividadeRESUMO
The design and synthesis of a novel class of human bradykinin B1 antagonists featuring difluoroethyl ether and isoxazole carboxamide moieties are disclosed. Compound 7g displayed excellent pharmacokinetic properties, efficient ex vivo receptor occupancy, and low potential for P450 induction via PXR activation.
Assuntos
Antagonistas de Receptor B1 da Bradicinina , Isoxazóis/farmacologia , Receptores de Esteroides/efeitos dos fármacos , Administração Oral , Animais , Disponibilidade Biológica , Cães , Humanos , Isoxazóis/farmacocinética , Macaca mulatta , Receptor de Pregnano X , Ratos , Ratos Sprague-DawleyRESUMO
A series of carbo- and heterocyclic alpha-hydroxy amide-derived bradykinin B1 antagonists was prepared and evaluated. A 4,4-difluorocyclohexyl alpha-hydroxy amide was incorporated along with a 2-methyl tetrazole in lieu of an oxadiazole to afford a suitable compound with good pharmacokinetic properties, CNS penetration, and clearance by multiple metabolic pathways.
Assuntos
Amidas/síntese química , Amidas/farmacologia , Antagonistas de Receptor B1 da Bradicinina , Tetrazóis/síntese química , Tetrazóis/farmacologia , Amidas/química , Amidas/farmacocinética , Animais , Sistema Nervoso Central/efeitos dos fármacos , Técnicas de Química Combinatória , Desenho de Fármacos , Humanos , Estrutura Molecular , Ratos , Relação Estrutura-Atividade , Tetrazóis/química , Tetrazóis/farmacocinéticaRESUMO
Antagonism of the bradykinin B(1) receptor represents a potential treatment for chronic pain and inflammation. Novel antagonists incorporating alpha-hydroxy amides were designed that display low-nanomolar affinity for the human bradykinin B(1) receptor and good bioavailability in the rat and dog. In addition, these functionally active compounds show high passive permeability and low susceptibility to phosphoglycoprotein mediated efflux, predictive of good CNS exposure.
Assuntos
Amidas/farmacologia , Antagonistas de Receptor B1 da Bradicinina , Amidas/química , Amidas/farmacocinética , Animais , Disponibilidade Biológica , Barreira Hematoencefálica , Inibidores das Enzimas do Citocromo P-450 , Cães , Meia-Vida , Humanos , Ratos , Ratos Sprague-Dawley , Relação Estrutura-AtividadeRESUMO
Identification of ligands that selectively activate the M1 muscarinic signaling pathway has been sought for decades to treat a range of neurological and cognitive disorders. Herein, we describe the optimization efforts focused on addressing key physicochemical and safety properties, ultimately leading to the clinical candidate MK-7622, a highly selective positive allosteric modulator of the M1 muscarinic receptor that has entered Phase II studies in patients with Alzheimer's disease.
RESUMO
A series of biphenylaminocyclopropane carboxamide based bradykinin B1 receptor antagonists has been developed that possesses good pharmacokinetic properties and is CNS penetrant. Discovery that the replacement of the trifluoropropionamide in the lead structure with polyhaloacetamides, particularly a trifluoroacetamide, significantly reduced P-glycoprotein mediated efflux for the series proved essential. One of these novel bradykinin B1 antagonists (13b) also exhibited suitable pharmacokinetic properties and efficient ex vivo receptor occupancy for further development as a novel approach for the treatment of pain and inflammation.
Assuntos
Acetamidas/síntese química , Amidas/síntese química , Compostos de Aminobifenil/síntese química , Benzoatos/síntese química , Antagonistas de Receptor B1 da Bradicinina , Encéfalo/metabolismo , Ciclopropanos/síntese química , Medula Espinal/metabolismo , Acetamidas/farmacocinética , Acetamidas/farmacologia , Administração Oral , Amidas/farmacocinética , Amidas/farmacologia , Compostos de Aminobifenil/farmacocinética , Compostos de Aminobifenil/farmacologia , Analgésicos/síntese química , Analgésicos/química , Analgésicos/farmacologia , Animais , Animais Geneticamente Modificados , Anti-Inflamatórios não Esteroides/síntese química , Anti-Inflamatórios não Esteroides/química , Anti-Inflamatórios não Esteroides/farmacologia , Benzoatos/farmacocinética , Benzoatos/farmacologia , Disponibilidade Biológica , Barreira Hematoencefálica/metabolismo , Células CHO , Chlorocebus aethiops , Cricetinae , Cricetulus , Ciclopropanos/farmacocinética , Ciclopropanos/farmacologia , Feminino , Humanos , Macaca mulatta , Masculino , Camundongos , Coelhos , Ensaio Radioligante , Ratos , Especificidade da Espécie , Relação Estrutura-AtividadeRESUMO
Leucine-rich repeat kinase 2 (LRRK2) is a large, multidomain protein which contains a kinase domain and GTPase domain among other regions. Individuals possessing gain of function mutations in the kinase domain such as the most prevalent G2019S mutation have been associated with an increased risk for the development of Parkinson's disease (PD). Given this genetic validation for inhibition of LRRK2 kinase activity as a potential means of affecting disease progression, our team set out to develop LRRK2 inhibitors to test this hypothesis. A high throughput screen of our compound collection afforded a number of promising indazole leads which were truncated in order to identify a minimum pharmacophore. Further optimization of these indazoles led to the development of MLi-2 (1): a potent, highly selective, orally available, brain-penetrant inhibitor of LRRK2.
Assuntos
Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Indazóis/química , Indazóis/farmacologia , Serina-Treonina Proteína Quinase-2 com Repetições Ricas em Leucina/antagonistas & inibidores , Animais , Encéfalo/metabolismo , Inibidores Enzimáticos/administração & dosagem , Inibidores Enzimáticos/farmacocinética , Humanos , Indazóis/administração & dosagem , Indazóis/farmacocinética , Serina-Treonina Proteína Quinase-2 com Repetições Ricas em Leucina/metabolismo , Masculino , Simulação de Acoplamento Molecular , Doença de Parkinson/tratamento farmacológico , Doença de Parkinson/enzimologia , Ratos , Ratos WistarRESUMO
A novel HIV protease inhibitor was designed using a morpholine core as the aspartate binding group. Analysis of the crystal structure of the initial lead bound to HIV protease enabled optimization of enzyme potency and antiviral activity. This afforded a series of potent orally bioavailable inhibitors of which MK-8718 was identified as a compound with a favorable overall profile.
RESUMO
RATIONALE: The current standards of care for Alzheimer's disease, acetylcholinesterase inhibitors, have limited efficacy due to a host of mechanism-related side effects arising from indiscriminate activation of muscarinic and nicotinic receptors. The M1 muscarinic receptor is predominantly expressed in the brain in regions involved in cognition, and therefore selective activation of the M1 receptor would be expected to boost cognitive performance with reduced risk of peripheral side effects. OBJECTIVES: Here we investigated whether the selective M1 muscarinic receptor positive allosteric modulator, PQCA, improves cognitive performance and cerebral blood flow. RESULTS: PQCA attenuated a scopolamine-induced deficit in novel object recognition in rat, self-ordered spatial search in cynomolgus macaque, and the object retrieval detour task in rhesus macaque. Beneficial effects in each of these assays and species were observed at similar plasma drug concentrations. Furthermore, at similar drug concentrations that were effective in the behavioral studies, PQCA increased blood flow in the frontal cortex of mice, providing a translational biomarker that could be used to guide dose selection for clinical studies. CONCLUSIONS: These findings provide a framework for appropriately testing an M1 selective compound in patients with Alzheimer's disease.
Assuntos
Encéfalo/efeitos dos fármacos , Cognição/efeitos dos fármacos , Piperidinas/farmacologia , Quinolizinas/farmacologia , Receptor Muscarínico M1/efeitos dos fármacos , Regulação Alostérica , Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/fisiopatologia , Animais , Encéfalo/irrigação sanguínea , Transtornos Cognitivos/tratamento farmacológico , Transtornos Cognitivos/etiologia , Transtornos Cognitivos/fisiopatologia , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Feminino , Macaca fascicularis , Macaca mulatta , Masculino , Camundongos , Piperidinas/administração & dosagem , Quinolizinas/administração & dosagem , Ratos , Ratos Wistar , Receptor Muscarínico M1/metabolismo , Fluxo Sanguíneo Regional/efeitos dos fármacos , Escopolamina/toxicidade , Especificidade da EspécieRESUMO
Selective activation of the M1 muscarinic receptor via positive allosteric modulation represents an approach to treat the cognitive decline in patients with Alzheimer's disease. A series of amides were examined as a replacement for the carboxylic acid moiety in a class of quinolizidinone carboxylic acid M1 muscarinic receptor positive allosteric modulators, and leading pyran 4o and cyclohexane 5c were found to possess good potency and in vivo efficacy.
RESUMO
One approach to ameliorate the cognitive decline in Alzheimer's disease (AD) has been to restore neuronal signaling from the basal forebrain cholinergic system via the activation of the M(1) muscarinic receptor. A number of nonselective M(1) muscarinic agonists have previously shown positive effects on cognitive behaviors in AD patients, but were limited due to cholinergic adverse events thought to be mediated by the activation of the M(2) to M(5) subtypes. One strategy to confer selectivity for M(1) is the identification of positive allosteric modulators, which would target an allosteric site on the M(1) receptor rather than the highly conserved orthosteric acetylcholine binding site. Quinoline carboxylic acids have been previously identified as highly selective M(1) positive allosteric modulators with good pharmacokinetic and in vivo properties. Herein is described the optimization of a novel quinolizidinone carboxylic acid scaffold with 4-cyanopiperidines being a key discovery in terms of enhanced activity. In particular, modulator 4i gave high plasma free fractions, enhanced central nervous system (CNS) exposure, was efficacious in a rodent in vivo model of cognition, and afforded good physicochemical properties suitable for further preclinical evaluation.
Assuntos
Colinérgicos/síntese química , Nitrilas/síntese química , Nootrópicos/síntese química , Piperidinas/síntese química , Quinolizidinas/síntese química , Quinolizinas/síntese química , Receptor Muscarínico M1/fisiologia , Regulação Alostérica , Animais , Disponibilidade Biológica , Células CHO , Colinérgicos/química , Colinérgicos/farmacologia , Cricetinae , Cricetulus , Medo/efeitos dos fármacos , Humanos , Masculino , Camundongos , Nitrilas/química , Nitrilas/farmacologia , Nootrópicos/química , Nootrópicos/farmacologia , Piperidinas/química , Piperidinas/farmacologia , Quinolizidinas/química , Quinolizidinas/farmacologia , Quinolizinas/química , Quinolizinas/farmacologia , Relação Estrutura-AtividadeRESUMO
Positive allosteric modulation of the M1 muscarinic receptor represents an approach to treat the cognitive decline in patients with Alzheimer's disease. Replacement of a quinolone ring system in a quinolone carboxylic acid series of M1 modulators with a quinolizidinone bearing a basic amine linkage led to a series of compounds with higher free fraction, enhanced CNS exposure, and improved efficacy in rodent in vivo models of cognition.
RESUMO
SAR study of the biphenyl region of cyclopropanecarboxamide derived bradykinin B(1) antagonists was examined. Incorporation of a pyridine in place of the proximal phenyl ring and chlorination of the distal phenyl ring proved to be well tolerated and provided compounds with improved pharmacokinetic profiles, CNS penetration, and enhanced receptor occupancy.
Assuntos
Amidas/química , Antagonistas de Receptor B1 da Bradicinina , Animais , Sistema Nervoso Central/efeitos dos fármacos , Química Farmacêutica/métodos , Cloro/química , Ciclopropanos/química , Desenho de Fármacos , Humanos , Modelos Químicos , Fenol/química , Piridinas/química , Ratos , Relação Estrutura-AtividadeRESUMO
A series of 2,3-diaminopyridine bradykinin B(1) antagonists was modified to mitigate the potential for bioactivation. Removal of the 3-amino group and incorporation of basic 5-piperazinyl carboxamides at the pyridine 5-position provided compounds with high affinity for the human B(1) receptor.
Assuntos
Antagonistas de Receptor B1 da Bradicinina , Piperazinas/farmacologia , Humanos , Modelos Moleculares , Piperazinas/químicaRESUMO
SAR study of the biphenyl region of 2,3-diaminopyridine bradykinin B1 antagonists was investigated with non-aromatic carbo- and heterocyclic rings. A piperidine ring was found to be a good replacement for the proximal phenyl ring while replacement of the distal phenyl was optimal with a cyclohexyl group leading to a dramatic improvement in affinity for the B1 receptor.