RESUMO
Severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) continues to be a global threat due to its ability to evolve and generate new subvariants, leading to new waves of infection. Additionally, other coronaviruses like Middle East respiratory syndrome coronavirus (MERS-CoV, formerly known as hCoV-EMC), which first emerged in 2012, persist and continue to present a threat of severe illness to humans. The continued identification of novel coronaviruses, coupled with the potential for genetic recombination between different strains, raises the possibility of new coronavirus clades of global concern emerging. As a result, there is a pressing need for pan-CoV therapeutic drugs and vaccines. After the extensive optimization of an HCV protease inhibitor screening hit, a novel 3CLPro inhibitor (MK-7845) was discovered and subsequently profiled. MK-7845 exhibited nanomolar in vitro potency with broad spectrum activity against a panel of clinical SARS-CoV-2 subvariants and MERS-CoV. Furthermore, when administered orally, MK-7845 demonstrated a notable reduction in viral burdens by >6 log orders in the lungs of transgenic mice infected with SARS-CoV-2 (K18-hACE2 mice) and MERS-CoV (K18-hDDP4 mice).
Assuntos
Antivirais , SARS-CoV-2 , Animais , Camundongos , SARS-CoV-2/efeitos dos fármacos , Humanos , Antivirais/farmacologia , Proteases 3C de Coronavírus/antagonistas & inibidores , Coronavírus da Síndrome Respiratória do Oriente Médio/efeitos dos fármacos , Coronavírus da Síndrome Respiratória do Oriente Médio/genética , Tratamento Farmacológico da COVID-19 , Inibidores de Proteases/farmacologia , COVID-19/virologia , Infecções por Coronavirus/tratamento farmacológico , Infecções por Coronavirus/virologiaRESUMO
As SARS-CoV-2 continues to circulate, antiviral treatments are needed to complement vaccines. The virus's main protease, 3CLPro, is an attractive drug target in part because it recognizes a unique cleavage site, which features a glutamine residue at the P1 position and is not utilized by human proteases. Herein, we report the invention of MK-7845, a novel reversible covalent 3CLPro inhibitor. While most covalent inhibitors of SARS-CoV-2 3CLPro reported to date contain an amide as a Gln mimic at P1, MK-7845 bears a difluorobutyl substituent at this position. SAR analysis and X-ray crystallographic studies indicate that this group interacts with His163, the same residue that forms a hydrogen bond with the amide substituents typically found at P1. In addition to promising in vivo efficacy and an acceptable projected human dose with unboosted pharmacokinetics, MK-7845 exhibits favorable properties for both solubility and absorption that may be attributable to the unusual difluorobutyl substituent.
Assuntos
COVID-19 , Glutamina , Humanos , Glutamina/química , SARS-CoV-2 , Cisteína Endopeptidases/química , Invenções , Inibidores de Proteases/farmacologia , Amidas , Antivirais/farmacologia , Antivirais/químicaRESUMO
PDE10A is an important regulator of striatal signaling that, when inhibited, can normalize dysfunctional activity. Given the involvement of dysfunctional striatal activity with schizophrenia, PDE10A inhibition represents a potentially novel means for its treatment. With the goal of developing PDE10A inhibitors, early optimization of a fragment hit through rational design led to a series of potent pyrimidine PDE10A inhibitors that required further improvements in physicochemical properties, off-target activities, and pharmacokinetics. Herein we describe the discovery of an isomeric pyrimidine series that addresses the liabilities seen with earlier compounds and resulted in the invention of compound 18 (MK-8189), which is currently in Phase 2b clinical development for the treatment of schizophrenia.
Assuntos
Inibidores de Fosfodiesterase , Esquizofrenia , Humanos , Cristalografia por Raios X , Inibidores de Fosfodiesterase/farmacologia , Inibidores de Fosfodiesterase/uso terapêutico , Inibidores de Fosfodiesterase/química , Diester Fosfórico Hidrolases/metabolismo , Pirimidinas/farmacologia , Pirimidinas/uso terapêutico , Pirimidinas/química , Esquizofrenia/tratamento farmacológico , Relação Estrutura-AtividadeRESUMO
As part of a drug discovery effort to identify potent inhibitors of NaV1.7 for the treatment of pain, we observed that inhibitors produced unexpected cardiovascular and respiratory effects in vivo. Specifically, inhibitors administered to rodents produced changes in cardiovascular parameters and respiratory cessation. We sought to determine the mechanism of the in vivo adverse effects by studying the selectivity of the compounds on NaV1.5, NaV1.4, and NaV1.6 in in vitro and ex vivo assays. Inhibitors lacking sufficient NaV1.7 selectivity over NaV1.6 were associated with respiratory cessation after in vivo administration to rodents. Effects on respiratory rate in rats were consistent with effects in an ex vivo hemisected rat diaphragm model and in vitro NaV1.6 potency. Furthermore, direct blockade of the phrenic nerve signaling was observed at exposures known to cause respiratory cessation in rats. Collectively, these results support a significant role for NaV1.6 in phrenic nerve signaling and respiratory function.
Assuntos
Canal de Sódio Disparado por Voltagem NAV1.7 , Insuficiência Respiratória , Animais , Dor , Nervo Frênico , Ratos , Insuficiência Respiratória/tratamento farmacológicoRESUMO
The voltage-gated sodium channel Nav1.7 continues to be a high-profile target for the treatment of various pain afflictions due to its strong human genetic validation. While isoform selective molecules have been discovered and advanced into the clinic, to date, this target has yet to bear fruit in the form of marketed therapeutics for the treatment of pain. Lead optimization efforts over the past decade have focused on selectivity over Nav1.5 due to its link to cardiac side effects as well as the translation of preclinical efficacy to man. Inhibition of Nav1.6 was recently reported to yield potential respiratory side effects preclinically, and this finding necessitated a modified target selectivity profile. Herein, we report the continued optimization of a novel series of arylsulfonamide Nav1.7 inhibitors to afford improved selectivity over Nav1.6 while maintaining rodent oral bioavailability through the use of a novel multiparameter optimization (MPO) paradigm. We also report in vitro-in vivo correlations from Nav1.7 electrophysiology protocols to preclinical models of efficacy to assist in projecting clinical doses. These efforts produced inhibitors such as compound 19 with potency against Nav1.7, selectivity over Nav1.5 and Nav1.6, and efficacy in behavioral models of pain in rodents as well as inhibition of rhesus olfactory response indicative of target modulation.
RESUMO
Humans with loss-of-function mutations in the Nav1.7 channel gene (SCN9A) show profound insensitivity to pain, whereas those with gain-of-function mutations can have inherited pain syndromes. Therefore, inhibition of the Nav1.7 channel with a small molecule has been considered a promising approach for the treatment of various human pain conditions. To date, clinical studies conducted using selective Nav1.7 inhibitors have not provided analgesic efficacy sufficient to warrant further investment. Clinical studies to date used multiples of in vitro IC50 values derived from electrophysiological studies to calculate anticipated human doses. To increase the chance of clinical success, we developed rhesus macaque models of action potential propagation, nociception, and olfaction, to measure Nav1.7 target modulation in vivo. The potent and selective Nav1.7 inhibitors SSCI-1 and SSCI-2 dose-dependently blocked C-fiber nociceptor conduction in microneurography studies and inhibited withdrawal responses to noxious heat in rhesus monkeys. Pharmacological Nav1.7 inhibition also reduced odor-induced activation of the olfactory bulb (OB), measured by functional magnetic resonance imaging (fMRI) studies consistent with the anosmia reported in Nav1.7 loss-of-function patients. These data demonstrate that it is possible to measure Nav1.7 target modulation in rhesus macaques and determine the plasma concentration required to produce a predetermined level of inhibition. The calculated plasma concentration for preclinical efficacy could be used to guide human efficacious exposure estimates. Given the translatable nature of the assays used, it is anticipated that they can be also used in phase 1 clinical studies to measure target modulation and aid in the interpretation of phase 1 clinical data.
Assuntos
Canal de Sódio Disparado por Voltagem NAV1.7 , Dor , Animais , Humanos , Macaca mulatta , Nociceptividade , NociceptoresRESUMO
Studies on human genetics have suggested that inhibitors of the Nav1.7 voltage-gated sodium channel hold considerable promise as therapies for the treatment of chronic pain syndromes. Herein, we report novel, peripherally-restricted benzoxazolinone aryl sulfonamides as potent Nav1.7 inhibitors with excellent selectivity against the Nav1.5 isoform, which is expressed in the heart muscle. Elaboration of initial lead compound 3d afforded exemplar 13, which featured attractive physicochemical properties, outstanding lipophilic ligand efficiency and pharmacological selectivity against Nav1.5 exceeding 1000-fold. Key structure-activity relationships associated with oral bioavailability were leveraged to discover compound 17, which exhibited a comparable potency/selectivity profile as well as full efficacy following oral administration in a preclinical model indicative of antinociceptive behavior.
Assuntos
Analgésicos/farmacologia , Benzoxazóis/farmacologia , Canal de Sódio Disparado por Voltagem NAV1.7/metabolismo , Dor/tratamento farmacológico , Sulfonamidas/farmacologia , Administração Oral , Analgésicos/administração & dosagem , Analgésicos/química , Animais , Benzoxazóis/administração & dosagem , Benzoxazóis/química , Disponibilidade Biológica , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Formaldeído/administração & dosagem , Humanos , Camundongos , Estrutura Molecular , Miócitos de Músculo Liso/efeitos dos fármacos , Miócitos de Músculo Liso/metabolismo , Dor/induzido quimicamente , Ratos , Relação Estrutura-Atividade , Sulfonamidas/administração & dosagem , Sulfonamidas/químicaRESUMO
The voltage-gated sodium channel Nav1.7 is a genetically validated target for the treatment of pain with gain-of-function mutations in man eliciting a variety of painful disorders and loss-of-function mutations affording insensitivity to pain. Unfortunately, drugs thought to garner efficacy via Nav1 inhibition have undesirable side effect profiles due to their lack of selectivity over channel isoforms. Herein we report the discovery of a novel series of orally bioavailable arylsulfonamide Nav1.7 inhibitors with high levels of selectivity over Nav1.5, the Nav isoform responsible for cardiovascular side effects, through judicious use of parallel medicinal chemistry and physicochemical property optimization. This effort produced inhibitors such as compound 5 with excellent potency, selectivity, behavioral efficacy in a rodent pain model, and efficacy in a mouse itch model suggestive of target modulation.
Assuntos
Sulfonamidas/química , Bloqueadores do Canal de Sódio Disparado por Voltagem/química , Administração Oral , Animais , Modelos Animais de Doenças , Avaliação Pré-Clínica de Medicamentos , Meia-Vida , Concentração Inibidora 50 , Camundongos , Canal de Sódio Disparado por Voltagem NAV1.7/química , Canal de Sódio Disparado por Voltagem NAV1.7/metabolismo , Nitrogênio/química , Dor/tratamento farmacológico , Isoformas de Proteínas/antagonistas & inibidores , Isoformas de Proteínas/metabolismo , Ratos , Relação Estrutura-Atividade , Sulfonamidas/farmacocinética , Sulfonamidas/uso terapêutico , Bloqueadores do Canal de Sódio Disparado por Voltagem/farmacocinética , Bloqueadores do Canal de Sódio Disparado por Voltagem/uso terapêuticoRESUMO
Investigation of a novel amino-aza-benzimidazolone structural class of positive allosteric modulators (PAMs) of metabotropic glutamate receptor 2 (mGluR2) identified [2.2.2]-bicyclic amine 12 as an intriguing lead structure due to its promising physicochemical properties and lipophilic ligand efficiency (LLE). Further optimization led to chiral amide 18, which exhibited strong in vitro activity and attractive pharmacokinetic (PK) properties. Hypothesis-driven target design identified compound 21 as a potent, highly selective, orally bioavailable mGluR2 PAM, which addressed a CYP time-dependent inhibition (TDI) liability of 18, while maintaining excellent drug-like properties with robust in vivo activity in a clinically validated model of antipsychotic potential.
RESUMO
Optimization of a benzimidazolone template for potency and physical properties revealed 5-aryl-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-ones as a key template on which to develop a new series of mGlu2 positive allosteric modulators (PAMs). Systematic investigation of aryl-SAR led to the identification of compound 27 as a potent and highly selective mGlu2 PAM with sufficient pharmacokinetics to advance to preclinical models of psychosis. Gratifyingly, compound 27 showed full efficacy in the PCP- and MK-801-induced hyperlocomotion assay in rats at CSF concentrations consistent with mGlu2 PAM potency.
Assuntos
Imidazóis/química , Piridinas/química , Piridonas/química , Receptores de Glutamato Metabotrópico/química , Regulação Alostérica , Animais , Modelos Animais de Doenças , Avaliação Pré-Clínica de Medicamentos , Imidazóis/sangue , Imidazóis/farmacologia , Imidazóis/uso terapêutico , Locomoção/efeitos dos fármacos , Ligação Proteica , Transtornos Psicóticos/tratamento farmacológico , Transtornos Psicóticos/patologia , Piridinas/farmacologia , Piridinas/uso terapêutico , Piridonas/sangue , Piridonas/farmacologia , Ratos , Receptores de Glutamato Metabotrópico/metabolismo , Relação Estrutura-AtividadeRESUMO
A series of 3-substituted aminocyclopentanes has been identified as highly potent and selective NR2B receptor antagonists. Incorporation of a 1,2,4-oxadiazole linker and substitution of the pendant phenyl ring led to the discovery of orally bioavailable analogues that showed efficient NR2B receptor occupancy in rats. Unlike nonselective NMDA antagonists, the NR2B-selective antagonist 22 showed no adverse affects on motor coordination in the rotarod assay at high dose. Compound 22 was efficacious following oral administration in a spinal nerve ligation model of neuropathic pain and in an acute model of Parkinson's disease in a dose dependent manner.
Assuntos
Ciclopentanos/síntese química , Ciclopentanos/farmacologia , Descoberta de Drogas/métodos , Antagonistas de Aminoácidos Excitatórios/síntese química , Antagonistas de Aminoácidos Excitatórios/farmacologia , Oxidiazóis/síntese química , Oxidiazóis/farmacologia , Pirimidinas/síntese química , Pirimidinas/farmacologia , Receptores de N-Metil-D-Aspartato/antagonistas & inibidores , Administração Oral , Animais , Benzopiranos/metabolismo , Disponibilidade Biológica , Catalepsia/induzido quimicamente , Catalepsia/tratamento farmacológico , Cães , Canal de Potássio ERG1 , Canais de Potássio Éter-A-Go-Go/antagonistas & inibidores , Canais de Potássio Éter-A-Go-Go/metabolismo , Feminino , Meia-Vida , Indicadores e Reagentes , Isomerismo , Ligadura , Macaca mulatta , Masculino , Neuralgia/tratamento farmacológico , Doença de Parkinson/tratamento farmacológico , Piperidinas/metabolismo , Ratos , Ratos Sprague-Dawley , Nervos Espinhais/patologiaRESUMO
Hit to lead optimization of (5R)-5-hexyl-3-phenyl-1,3-oxazolidin-2-one as a positive allosteric modulator of mGluR2 is described. Improvements in potency and metabolic stability were achieved through SAR on both ends of the oxazolidinone. An optimized lead compound was found to be brain penetrant and active in a rat ketamine-induced hyperlocomotion model for antipsychotic activity.
Assuntos
Oxazolidinonas/química , Receptores de Glutamato Metabotrópico/metabolismo , Esquizofrenia/tratamento farmacológico , Regulação Alostérica , Animais , Antipsicóticos , Ketamina/toxicidade , Oxazolidinonas/síntese química , Oxazolidinonas/farmacologia , Ratos , Receptores de Glutamato Metabotrópico/agonistas , Relação Estrutura-AtividadeRESUMO
This article describes recent advances in the development and biological evaluation of allosteric and ATP-competitive small molecule inhibitors for the serine/threonine kinase Akt (protein kinase B, PKB). Unregulated activation of the PI3K/Akt/PTEN pathway is a prominent feature of many human cancers and Akt is over-expressed or activated in all major cancers making Akt an exciting new target for cancer therapy. The development of Akt inhibitors has been complicated and hampered by the presence of three Akt isozymes, (Akt1, Akt2 and Akt3) which differ in function and tissue distribution, as well as a lack of Akt specific inhibitors. In the past 18 months, a large number of reports have appeared describing the discovery and development of allosteric Akt kinase inhibitors and classical ATP-competitive Akt kinase inhibitors. This review will discuss the PI3K/Akt/PTEN pathway, allosteric and ATP-competitive Akt kinase inhibitors, their biological evaluation and progress towards target validation.
Assuntos
Trifosfato de Adenosina/metabolismo , Inibidores de Fosfoinositídeo-3 Quinase , Inibidores de Proteínas Quinases/farmacologia , Proteínas Proto-Oncogênicas c-akt/antagonistas & inibidores , Transdução de Sinais/fisiologia , Regulação Alostérica/efeitos dos fármacos , Regulação Alostérica/fisiologia , Animais , Inibidores Enzimáticos/farmacologia , Humanos , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais/efeitos dos fármacos , Tecnologia Farmacêutica/tendênciasRESUMO
This article describes recent advances in the development and biological evaluation of small molecule inhibitors for the serine/threonine kinase Akt (PKB). Akt plays a pivotal role in cell survival and proliferation through a number of downstream effectors. Recent studies indicate that unregulated activation of the PI3K/Akt pathway is a prominent feature of many human cancers and Akt is over-expressed or activated in all major cancers. Akt is considered an attractive target for cancer therapy and inhibition of Akt alone or in combination with standard cancer chemotherapeutics has been postulated to reduce the apoptotic threshold and preferentially kill cancer cells. The development of specific and potent inhibitors will allow this hypothesis to be tested in animals. Recently, several series of small molecule, ATP-competitive inhibitors have been reported with a range of Akt potencies and selectivities. Phosphatidylinositol (PI) analogs have been reported to inhibit Akt, but these inhibitors may also have specificity problems with respect to other pleckstrin homology (PH) domain containing proteins and may have poor bioavailability. In addition, novel allosteric inhibitors have been reported which are PH domain dependent, exhibit selectivity for the individual Akt isozymes and inhibit the activity and the activation of Akt. Compounds within these classes Akt inhibitors have sufficient potency and specificity to test for tumor efficacy in animal models and recently reported preliminary experiments are reviewed.
Assuntos
Trifosfato de Adenosina/antagonistas & inibidores , Inibidores de Proteínas Quinases/química , Proteínas Proto-Oncogênicas c-akt/antagonistas & inibidores , Regulação Alostérica/efeitos dos fármacos , Antineoplásicos/química , Ligação Competitiva , Desenho de Fármacos , Humanos , Inibidores de Proteínas Quinases/farmacologiaRESUMO
Over activation of the NMDA receptor complex has been implicated in a number of neurological conditions. The use of NMDA antagonists as therapeutic agents has been limited by serious cognitive and motor side effects. Significant efforts have been reported in the development of NR2B subtype-selective antagonists, which have shown efficacy without the side effects observed with nonspecific NMDA antagonists. Classical ifenprodil-like molecules containing benzyl- and phenylpiperidines attached to a phenol or an appropriate isostere by a linker have provided valuable chemical leads as potential therapeutic agents. In this review, recent efforts in the discovery and development of structurally unique NR2B subtype-selective NMDA antagonists that do not fit the classical "ifenprodil-like" pharmacophore will be discussed.
Assuntos
Antagonistas de Aminoácidos Excitatórios/farmacologia , Receptores de N-Metil-D-Aspartato/antagonistas & inibidores , Animais , Antagonistas de Aminoácidos Excitatórios/efeitos adversos , Antagonistas de Aminoácidos Excitatórios/química , Humanos , Estrutura MolecularRESUMO
This article describes recent advances in the development of subtype-selective, noncompetitive modulators of metabotropic glutamate receptor subtype 1 (mGluR1). mGluR1 plays an important role in modulating synaptic transmission and neuronal excitability via intracellular signal transduction pathways and has been implicated in a number of CNS disorders. Allosteric modulation of mGluR1 by potentiation and antagonism occurs through binding to the seven transmembrane domain. In addition to blocking agonist-dependent responses, many of the antagonists also show inverse-agonist activity by blocking constitutive receptor activity. Highly potent and selective mGluR1 radioligands have been used to evaluate receptor binding in vivo and in vitro. Some of these novel agents have demonstrated high levels of CNS exposure and receptor occupancy in vivo, as well as efficacy in a number of preclinical models of neurological disorders.
Assuntos
Agonistas de Aminoácidos Excitatórios/farmacologia , Antagonistas de Aminoácidos Excitatórios/farmacologia , Receptores de Glutamato Metabotrópico , Regulação Alostérica , Animais , Desenho de Fármacos , Humanos , Receptores de Glutamato Metabotrópico/agonistas , Receptores de Glutamato Metabotrópico/antagonistas & inibidores , Receptores de Glutamato Metabotrópico/metabolismoRESUMO
We present a full report of our enantioselective synthesis of (-)-longithorone A (1). The synthesis was designed to test the feasibility of the biosynthetic proposal for 1 put forward by Schmitz involving intermolecular and transannular Diels-Alder reactions of two [12]-paracyclophane quinones. We have found that if the biosynthesis does involve these two Diels-Alder reactions, the intermolecular Diels-Alder reaction likely occurs before the transannular cycloaddition. The intermolecular Diels-Alder precursors, [12]-paracyclophanes 38, 49, 59, and 60, were prepared atropselectively, providing examples of ene-yne metathesis macrocyclization. The 1,3-disubstituted dienes produced from the macrocyclizations represent a previously unreported substitution pattern for intramolecular ene-yne metathesis. Protected benzylic hydroxyl stereocenters were used as removable atropisomer control elements and were installed by using a highly enantioselective vinylzinc addition to electron-rich benzaldehydes 26 and 27.
Assuntos
Hidrocarbonetos Aromáticos com Pontes/síntese química , Compostos Policíclicos/síntese química , Hidrocarbonetos Aromáticos com Pontes/química , Hidrocarbonetos Aromáticos com Pontes/metabolismo , Química Orgânica/métodos , Modelos Químicos , Estrutura Molecular , Compostos Policíclicos/química , Compostos Policíclicos/metabolismo , EstereoisomerismoRESUMO
An enantioseletive, biomimetic synthesis of (-)-longithorone A has been achieved using an intermolecular/transannular Diels-Alder sequence which provides some support for the proposed biosynthesis. The cycloaddition precursors were two [12]-paracyclophanes that were constructed with atropisomer control during ene-yne metathesis macrocyclizations.