RESUMO
Current therapies for chronic pain can have insufficient efficacy and lead to side effects, necessitating research of novel targets against pain. Although originally identified as an oncogene, Tropomyosin-related kinase A (TrkA) is linked to pain and elevated levels of NGF (the ligand for TrkA) are associated with chronic pain. Antibodies that block TrkA interaction with its ligand, NGF, are in clinical trials for pain relief. Here, we describe the identification of TrkA-specific inhibitors and the structural basis for their selectivity over other Trk family kinases. The X-ray structures reveal a binding site outside the kinase active site that uses residues from the kinase domain and the juxtamembrane region. Three modes of binding with the juxtamembrane region are characterized through a series of ligand-bound complexes. The structures indicate a critical pharmacophore on the compounds that leads to the distinct binding modes. The mode of interaction can allow TrkA selectivity over TrkB and TrkC or promiscuous, pan-Trk inhibition. This finding highlights the difficulty in characterizing the structure-activity relationship of a chemical series in the absence of structural information because of substantial differences in the interacting residues. These structures illustrate the flexibility of binding to sequences outside of-but adjacent to-the kinase domain of TrkA. This knowledge allows development of compounds with specificity for TrkA or the family of Trk proteins.
Assuntos
Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/farmacologia , Receptor trkA/antagonistas & inibidores , Receptor trkA/química , Sequência de Aminoácidos , Sítios de Ligação , Cristalografia por Raios X , Avaliação Pré-Clínica de Medicamentos , Humanos , Cinética , Glicoproteínas de Membrana/antagonistas & inibidores , Glicoproteínas de Membrana/química , Glicoproteínas de Membrana/genética , Modelos Moleculares , Conformação Proteica , Inibidores de Proteínas Quinases/síntese química , Receptor trkA/genética , Receptor trkB/antagonistas & inibidores , Receptor trkB/química , Receptor trkB/genética , Receptor trkC/antagonistas & inibidores , Receptor trkC/química , Receptor trkC/genética , Proteínas Recombinantes/química , Proteínas Recombinantes/efeitos dos fármacos , Proteínas Recombinantes/genética , Relação Estrutura-Atividade , Ressonância de Plasmônio de SuperfícieRESUMO
Selective inhibition of Kv1.5, which underlies the ultra-rapid delayed rectifier current, IKur, has been pursued as a treatment for atrial fibrillation. Here we describe the discovery of MK-1832, a Kv1.5 inhibitor with improved selectivity versus the off-target current IKs, whose inhibition has been associated with ventricular proarrhythmia. MK-1832 exhibits improved selectivity for IKur over IKs (>3000-fold versus 70-fold for MK-0448), consistent with an observed larger window between atrial and ventricular effects in vivo (>1800-fold versus 210-fold for MK-0448). MK-1832 also exhibits an improved preclinical pharmacokinetic profile consistent with projected once daily dosing in humans.
Assuntos
Canal de Potássio Kv1.5/antagonistas & inibidores , Piridinas/farmacologia , Descoberta de Drogas , Humanos , Piridinas/farmacocinética , Relação Estrutura-AtividadeRESUMO
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
A new series of CB2-selective agonists containing a benzimidazole core is reported. Design, synthesis, SAR and pharmacokinetic data for selected compounds are described.
Assuntos
Benzimidazóis/farmacologia , Desenho de Fármacos , Receptor CB2 de Canabinoide/agonistas , Benzimidazóis/síntese química , Benzimidazóis/química , Relação Dose-Resposta a Droga , Humanos , Modelos Moleculares , Estrutura Molecular , Relação Estrutura-AtividadeRESUMO
A series of methoxynaphthalene amides were prepared and evaluated as alternatives to quinolizidinone amide M1 positive allosteric modulators. A methoxy group was optimal for M1 activity and addressed key P-gp issues present in the aforementioned quinolizidinone amide series.
Assuntos
Amidas/química , Naftalenos/química , Quinolizidinas/química , Receptor Muscarínico M1/metabolismo , Regulação Alostérica , Amidas/síntese química , Amidas/metabolismo , Animais , Células CHO , Cricetinae , Cricetulus , Camundongos , Ligação Proteica , Receptor Muscarínico M1/química , Relação Estrutura-AtividadeRESUMO
Fused aromatics such as naphthalene were identified as highly potent and CNS penetrant M(1) positive allosteric modulators during an SAR study to replace the phenyl B-ring linkage.
Assuntos
Naftóis/química , Receptor Muscarínico M1/metabolismo , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/sangue , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/líquido cefalorraquidiano , Regulação Alostérica/efeitos dos fármacos , Animais , Ácidos Carboxílicos/química , Ácidos Carboxílicos/farmacologia , Humanos , Estrutura Molecular , Naftóis/farmacologia , Quinolonas/química , Quinolonas/farmacologia , Ratos , Relação Estrutura-AtividadeRESUMO
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 novel series of decahydroquinoline CB2 agonists is described. Optimization of the amide substituent led to improvements in CB2/CB1 selectivity as well as physical properties. Two key compounds were examined in the rat CFA model of acute inflammatory pain. A moderately selective CB2 agonist was active in this model. A CB2 agonist lacking functional CB1 activity was inactive in this model despite high in vivo exposure both peripherally and centrally.
Assuntos
Amidas/química , Analgésicos/química , Quinolinas/química , Receptor CB2 de Canabinoide/agonistas , Amidas/síntese química , Amidas/uso terapêutico , Analgésicos/síntese química , Analgésicos/uso terapêutico , Animais , Modelos Animais de Doenças , Humanos , Camundongos , Camundongos Transgênicos , Dor/tratamento farmacológico , Ratos , Receptor CB1 de Canabinoide/agonistas , Receptor CB1 de Canabinoide/metabolismo , Receptor CB2 de Canabinoide/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
A new series of imidazopyridine CB2 agonists is described. Structural optimization improved CB2/CB1 selectivity in this series and conferred physical properties that facilitated high in vivo exposure, both centrally and peripherally. Administration of a highly selective CB2 agonist in a rat model of analgesia was ineffective despite substantial CNS exposure, while administration of a moderately selective CB2/CB1 agonist exhibited significant analgesic effects.
Assuntos
Analgésicos/química , Piridinas/química , Receptor CB1 de Canabinoide/agonistas , Receptor CB2 de Canabinoide/agonistas , Analgésicos/síntese química , Analgésicos/uso terapêutico , Animais , Modelos Animais de Doenças , Adjuvante de Freund/farmacologia , Humanos , Hiperalgesia/tratamento farmacológico , Piridinas/síntese química , Piridinas/uso terapêutico , Ratos , Receptor CB1 de Canabinoide/metabolismo , Receptor CB2 de Canabinoide/metabolismoRESUMO
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
Incorporation of hydroxycycloalkyl fused pyridone carboxylic acids in lieu of quinolone carboxylic acids enhance free fraction without increased susceptibility to P-glycoprotein transport.
Assuntos
Ácidos Carboxílicos/farmacologia , Piridonas/química , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/metabolismo , Regulação Alostérica , Animais , Ácidos Carboxílicos/química , Camundongos , Transporte Proteico , RatosRESUMO
A new structural class of potent antagonists of the Neuropeptide S Receptor (NPSR) is reported. High-throughput screening identified a tricyclic imidazole antagonist of NPSR, and medicinal chemistry optimization of this structure was undertaken to improve potency against the receptor as well as CNS penetration. Detailed herein are synthetic and medicinal chemistry studies that led to the identification of antagonists 15 and NPSR-PI1, which demonstrate potent in vitro NPSR antagonism and central exposure in vivo.
Assuntos
Compostos Heterocíclicos com 3 Anéis/química , Imidazóis/química , Receptores de Neuropeptídeos/antagonistas & inibidores , Animais , Compostos Heterocíclicos com 3 Anéis/síntese química , Compostos Heterocíclicos com 3 Anéis/farmacologia , Ensaios de Triagem em Larga Escala , Humanos , Imidazóis/síntese química , Imidazóis/farmacologia , Ratos , Receptores de Neuropeptídeos/metabolismo , Relação Estrutura-AtividadeRESUMO
Replacement of a phenyl ring with N-linked heterocycles in a series of quinolone carboxylic acid M1 positive allosteric modulators was investigated. In particular, a pyrazole derivative exhibited improvements in potency, free fraction, and CNS exposure.
Assuntos
Ácidos Carboxílicos/síntese química , Compostos Heterocíclicos/síntese química , Pirazóis/síntese química , Quinolinas/síntese química , Regulação Alostérica , Animais , Células CHO , Ácidos Carboxílicos/química , Ácidos Carboxílicos/farmacologia , Linhagem Celular , Cricetinae , Cricetulus , Compostos Heterocíclicos/química , Compostos Heterocíclicos/farmacologia , Humanos , Estrutura Molecular , Pirazóis/química , Pirazóis/farmacologia , Quinolinas/química , Quinolinas/farmacologia , Ratos , Relação Estrutura-AtividadeRESUMO
Incorporation of pyridines and diazines into the biphenyl region of quinolone carboxylic acid derived M(1) positive allosteric modulators was investigated as a means of lowering plasma protein binding to enhance CNS exposure.
Assuntos
Proteínas Sanguíneas/química , Piridinas/química , Receptor Muscarínico M1/antagonistas & inibidores , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/metabolismo , Regulação Alostérica , Animais , Proteínas Sanguíneas/metabolismo , Humanos , Ligação Proteica , Piridinas/síntese química , Piridinas/farmacologia , Ratos , Receptor Muscarínico M1/metabolismo , Relação Estrutura-AtividadeRESUMO
Administration of Neuropeptide S (NPS) has been shown to produce arousal, that is, independent of novelty and to induce wakefulness by suppressing all stages of sleep, as demonstrated by EEG recordings in rat. Medicinal chemistry efforts have identified a quinolinone class of potent NPSR antagonists that readily cross the blood-brain barrier. We detail here optimization efforts resulting in the identification of a potent NPSR antagonist which dose-dependently and specifically inhibited (125)I-NPS binding in the CNS when administered to rats.
Assuntos
Receptores de Neuropeptídeos/antagonistas & inibidores , Amidas/síntese química , Amidas/química , Amidas/farmacologia , Animais , Barreira Hematoencefálica/metabolismo , Sistema Nervoso Central/metabolismo , Humanos , Radioisótopos do Iodo/química , Ligação Proteica , Quinolonas/síntese química , Quinolonas/química , Quinolonas/farmacologia , Ratos , Receptores de Neuropeptídeos/metabolismo , Relação Estrutura-AtividadeRESUMO
The PI3K pathway is considered a master regulator for cancer due to its frequent activation, making it an attractive target for pharmacologic intervention. While substantial efforts have been made to develop drugs targeting PI3K signaling, few drugs have been able to achieve the inhibition necessary for effective tumor control at tolerated doses. HSP90 is a chaperone protein that is overexpressed and activated in many tumors and as a consequence, small-molecule ligands of HSP90 are preferentially retained in tumors up to 20 times longer than in normal tissue. We hypothesize that the generation of conjugates that use a HSP90-targeting ligand and a payload such as copanlisib, may open the narrow therapeutic window of this and other PI3K inhibitors. In support of this hypothesis, we have generated a HSP90-PI3K drug conjugate, T-2143 and utilizing xenograft models, demonstrate rapid and sustained tumor accumulation of the conjugate, deep pathway inhibition, and superior efficacy than the PI3K inhibitor on its own. Selective delivery of T-2143 and the masking of the inhibitor active site was also able to mitigate a potentially dose-limiting side effect of copanlisib, hyperglycemia. These data demonstrate that by leveraging the preferential accumulation of HSP90-targeting ligands in tumors, we can selectively deliver a PI3K inhibitor leading to efficacy in multiple tumor models without hyperglycemia in mice. These data highlight a novel drug delivery strategy that allows for the potential opening of a narrow therapeutic window through specific tumor delivery of anticancer payloads and reduction of toxicity.
Assuntos
Sistemas de Liberação de Medicamentos , Proteínas de Choque Térmico HSP90/metabolismo , Neoplasias/tratamento farmacológico , Fosfatidilinositol 3-Quinases/química , Inibidores de Proteínas Quinases/farmacologia , Animais , Apoptose , Proliferação de Células , Feminino , Proteínas de Choque Térmico HSP90/química , Humanos , Camundongos , Camundongos Nus , Neoplasias/metabolismo , Neoplasias/patologia , Fosfatidilinositol 3-Quinases/metabolismo , Inibidores de Proteínas Quinases/química , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
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
Small cell lung cancer (SCLC) is an aggressive neuroendocrine carcinoma with a 95% mortality rate with no improvement to treatment in decades, and new therapies are desperately needed. PEN-221 is a miniaturized peptide-drug conjugate (â¼2 kDa) designed to target SCLC via a Somatostatin Receptor 2 (SSTR2)-targeting ligand and to overcome the high proliferation rate characteristic of this disease by using the potent cytotoxic payload, DM1. SSTR2 is an ideal target for a drug conjugate, as it is overexpressed in SCLC with limited normal tissue expression. In vitro, PEN-221 treatment of SSTR2-positive cells resulted in PEN-221 internalization and receptor-dependent inhibition of cellular proliferation. In vivo, PEN-221 exhibited rapid accumulation in SSTR2-positive SCLC xenograft tumors with quick clearance from plasma. Tumor accumulation was sustained, resulting in durable pharmacodynamic changes throughout the tumor, as evidenced by increases in the mitotic marker of G2-M arrest, phosphohistone H3, and increases in the apoptotic marker, cleaved caspase-3. PEN-221 treatment resulted in significant antitumor activity, including complete regressions in SSTR2-positive SCLC xenograft mouse models. Treatment was effective using a variety of dosing schedules and at doses below the MTD, suggesting flexibility of dosing schedule and potential for a large therapeutic window in the clinic. The unique attributes of the miniaturized drug conjugate allowed for deep tumor penetration and limited plasma exposure that may enable long-term dosing, resulting in durable tumor control. Collectively, these data suggest potential for antitumor activity of PEN-221 in patients with SSTR2-positive SCLC.