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1.
Circulation ; 148(2): 144-158, 2023 07 11.
Artículo en Inglés | MEDLINE | ID: mdl-37125593

RESUMEN

BACKGROUND: Inhibition of PCSK9 (proprotein convertase subtilisin/kexin type 9)-low density lipoprotein receptor interaction with injectable monoclonal antibodies or small interfering RNA lowers plasma low density lipoprotein-cholesterol, but despite nearly 2 decades of effort, an oral inhibitor of PCSK9 is not available. Macrocyclic peptides represent a novel approach to target proteins traditionally considered intractable to small-molecule drug design. METHODS: Novel mRNA display screening technology was used to identify lead chemical matter, which was then optimized by applying structure-based drug design enabled by novel synthetic chemistry to identify macrocyclic peptide (MK-0616) with exquisite potency and selectivity for PCSK9. Following completion of nonclinical safety studies, MK-0616 was administered to healthy adult participants in a single rising-dose Phase 1 clinical trial designed to evaluate its safety, pharmacokinetics, and pharmacodynamics. In a multiple-dose trial in participants taking statins, MK-0616 was administered once daily for 14 days to characterize the safety, pharmacokinetics, and pharmacodynamics (change in low density lipoprotein cholesterol). RESULTS: MK-0616 displayed high affinity (Ki = 5pM) for PCSK9 in vitro and sufficient safety and oral bioavailability preclinically to enable advancement into the clinic. In Phase 1 clinical studies in healthy adults, single oral doses of MK-0616 were associated with >93% geometric mean reduction (95% CI, 84-103) of free, unbound plasma PCSK9; in participants on statin therapy, multiple-oral-dose regimens provided a maximum 61% geometric mean reduction (95% CI, 43-85) in low density lipoprotein cholesterol from baseline after 14 days of once-daily dosing of 20 mg MK-0616. CONCLUSIONS: This work validates the use of mRNA display technology for identification of novel oral therapeutic agents, exemplified by the identification of an oral PCSK9 inhibitor, which has the potential to be a highly effective cholesterol lowering therapy for patients in need.


Asunto(s)
Anticolesterolemiantes , Inhibidores de Hidroximetilglutaril-CoA Reductasas , Hipercolesterolemia , Adulto , Humanos , Anticolesterolemiantes/efectos adversos , Colesterol , LDL-Colesterol , Inhibidores de Hidroximetilglutaril-CoA Reductasas/uso terapéutico , Péptidos/uso terapéutico , Proproteína Convertasa 9/genética , Proproteína Convertasa 9/metabolismo , Receptores de LDL/genética , Receptores de LDL/metabolismo
2.
J Org Chem ; 85(3): 1466-1475, 2020 02 07.
Artículo en Inglés | MEDLINE | ID: mdl-31660743

RESUMEN

The Myc transcription factor represents an "undruggable" target of high biological interest due to its central role in various cancers. An abbreviated form of the c-Myc protein, called Omomyc, consists of the Myc DNA-binding domain and a coiled-coil region to facilitate dimerization of the 90 amino acid polypeptide. Here we present our results to evaluate the synthesis of Omomyc using three complementary strategies: linear Fmoc solid-phase peptide synthesis (SPPS) using several advancements for difficult sequences, native chemical ligation from smaller peptide fragments, and a high-throughput bacterial expression and assay platform for rapid mutagenesis. This multifaceted approach allowed access to up to gram quantities of the mini-protein and permitted in vitro and in vivo SAR exploration of this modality. DNA-binding results and cellular activity confirm that Omomyc and analogues presented here, are potent binders of the E-box DNA engaged by Myc for transcriptional activation and that this 90-amino acid mini-protein is cell permeable and can inhibit proliferation of Myc-dependent cell lines. We also present additional results on covalent homodimerization through disulfide formation of the full-length mini-protein and show the coiled-coil region can be truncated while preserving both DNA binding and cellular activity. Altogether, our results highlight the ability of advanced peptide synthesis to achieve SAR tractability in a challenging synthetic modality.


Asunto(s)
ADN , Proteínas Proto-Oncogénicas c-myc , Línea Celular , ADN/metabolismo , Fragmentos de Péptidos , Unión Proteica , Proteínas Proto-Oncogénicas c-myc/genética , Proteínas Proto-Oncogénicas c-myc/metabolismo
3.
Bioconjug Chem ; 29(7): 2357-2369, 2018 07 18.
Artículo en Inglés | MEDLINE | ID: mdl-29923706

RESUMEN

Glucocorticoids (GCs) are excellent anti-inflammatory drugs but are dose-limited by on-target toxicity. We sought to solve this problem by delivering GCs to immune cells with antibody-drug conjugates (ADCs) using antibodies containing site-specific incorporation of a non-natural amino acid, novel linker chemistry for in vitro and in vivo stability, and existing and novel glucocorticoid receptor (GR) agonists as payloads. We directed fluticasone propionate to human antigen-presenting immune cells to afford GR activation that was dependent on the targeted antigen. However, mechanism of action studies pointed to accumulation of free payload in the tissue culture supernatant as the dominant driver of activity and indeed administration of the ADC to human CD74 transgenic mice failed to activate GR target genes in splenic B cells. Suspecting dissipation of released payload, we designed an ADC bearing a novel GR agonist payload with reduced permeability which afforded cell-intrinsic activity in human B cells. Our work shows that antibody-targeting offers significant potential for rescuing existing and new dose-limited drugs outside the field of oncology.


Asunto(s)
Anticuerpos Monoclonales/uso terapéutico , Antígenos de Diferenciación de Linfocitos B/inmunología , Linfocitos B/metabolismo , Sistemas de Liberación de Medicamentos/métodos , Glucocorticoides/administración & dosificación , Antígenos de Histocompatibilidad Clase II/inmunología , Inmunoconjugados/uso terapéutico , Animales , Antiinflamatorios/uso terapéutico , Linfocitos B/efectos de los fármacos , Desarrollo de Medicamentos , Estabilidad de Medicamentos , Fluticasona/administración & dosificación , Humanos , Ratones , Ratones Transgénicos , Receptores de Glucocorticoides/agonistas
4.
J Am Chem Soc ; 138(4): 1430-45, 2016 Feb 03.
Artículo en Inglés | MEDLINE | ID: mdl-26745435

RESUMEN

As part of an effort to examine the utility of antibody-drug conjugates (ADCs) beyond oncology indications, a novel pyrophosphate ester linker was discovered to enable the targeted delivery of glucocorticoids. As small molecules, these highly soluble phosphate ester drug linkers were found to have ideal orthogonal properties: robust plasma stability coupled with rapid release of payload in a lysosomal environment. Building upon these findings, site-specific ADCs were made between this drug linker combination and an antibody against human CD70, a receptor specifically expressed in immune cells but also found aberrantly expressed in multiple human carcinomas. Full characterization of these ADCs enabled procession to in vitro proof of concept, wherein ADCs 1-22 and 1-37 were demonstrated to afford potent, targeted delivery of glucocorticoids to a representative cell line, as measured by changes in glucocorticoid receptor-mediated gene mRNA levels. These activities were found to be antibody-, linker-, and payload-dependent. Preliminary mechanistic studies support the notion that lysosomal trafficking and enzymatic linker cleavage are required for activity and that the utility for the pyrophosphate linker may be general for internalizing ADCs as well as other targeted delivery platforms.


Asunto(s)
Difosfatos/química , Glucocorticoides/química , Inmunoconjugados/química , Ésteres
5.
Bioconjug Chem ; 27(9): 2081-8, 2016 09 21.
Artículo en Inglés | MEDLINE | ID: mdl-27469406

RESUMEN

In an effort to examine the utility of antibody-drug conjugates (ADCs) beyond oncology indications, a novel phosphate bridged Cathepsin B sensitive linker was developed to enable the targeted delivery of glucocorticoids. Phosphate bridging of the Cathepsin B sensitive linkers allows for payload attachment at an aliphatic alcohol. As small molecule drug-linkers, these aqueous soluble phosphate containing drug-linkers were found to have robust plasma stability coupled with rapid release of payload in a lysosomal environment. Site-specific ADCs were successfully made between these drug-linkers and an antibody against human CD70, a receptor specifically expressed in immune cells but also found aberrantly expressed in multiple human carcinomas. These ADCs demonstrated in vitro targeted delivery of glucocorticoids to a representative cell line as measured by changes in glucocorticoid receptor (GR) mediated gene mRNA levels. This novel linker expands the scope of potential ADC payloads by allowing an aliphatic alcohol to be a stable, yet cleavable attachment site. This phosphate linker may have broad utility for internalizing ADCs as well as other targeted delivery platforms.


Asunto(s)
Catepsina B/metabolismo , Inmunoconjugados/química , Inmunoconjugados/metabolismo , Fosfatos/química , Agua/química , Alcoholes/química , Carbonatos/química , Estabilidad de Medicamentos , Humanos , Lisosomas/metabolismo , Solubilidad
6.
Bioorg Med Chem Lett ; 26(4): 1260-4, 2016 Feb 15.
Artículo en Inglés | MEDLINE | ID: mdl-26810316

RESUMEN

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.


Asunto(s)
Imidazoles/química , Piridinas/química , Piridonas/química , Receptores de Glutamato Metabotrópico/química , Regulación Alostérica , Animales , Modelos Animales de Enfermedad , Evaluación Preclínica de Medicamentos , Imidazoles/sangre , Imidazoles/farmacología , Imidazoles/uso terapéutico , Locomoción/efectos de los fármacos , Unión Proteica , Trastornos Psicóticos/tratamiento farmacológico , Trastornos Psicóticos/patología , Piridinas/farmacología , Piridinas/uso terapéutico , Piridonas/sangre , Piridonas/farmacología , Ratas , Receptores de Glutamato Metabotrópico/metabolismo , Relación Estructura-Actividad
7.
Bioconjug Chem ; 25(5): 896-906, 2014 May 21.
Artículo en Inglés | MEDLINE | ID: mdl-24742200

RESUMEN

The application of small interfering (si)RNAs as potential therapeutic agents requires safe and effective methods for their delivery to the cytoplasm of the target cells and tissues. Recent studies have shown significant progress in the development of targeting reagents that facilitate the recognition of, and siRNA delivery to, specific cell types. Among recently reported delivery approaches, polymers with amphipathic properties have been used to enable endosome escape and cytosolic delivery. Here, we describe a linear amphipathic poly(amido amine) polymer conjugate system for the efficient siRNA delivery in vitro and in vivo. This polymer contains a novel amine bearing bis-acrylamide monomer designed for increasing amine density, which resulted in substantial improvement in liver uptake and RNAi activity compared to our previously reported poly(amido amine disulfide) polymer.1 The activity for this liver targeted delivery system was demonstrated in rodents and nonhuman primates.


Asunto(s)
Sistemas de Liberación de Medicamentos , Endosomas/metabolismo , Hepatocitos/metabolismo , Hígado/metabolismo , Poliaminas/química , ARN Interferente Pequeño/administración & dosificación , ARN Interferente Pequeño/farmacocinética , Animales , Endosomas/química , Femenino , Silenciador del Gen , Células Hep G2 , Hepatocitos/citología , Humanos , Hígado/citología , Macaca mulatta , Ratones , Estructura Molecular , Poliaminas/síntesis química , Poliaminas/metabolismo , ARN Interferente Pequeño/química , Ratas , Ratas Sprague-Dawley
8.
Bioconjug Chem ; 25(2): 296-307, 2014 Feb 19.
Artículo en Inglés | MEDLINE | ID: mdl-24409989

RESUMEN

Polymer based carriers that aid in endosomal escape have proven to be efficacious siRNA delivery agents in vitro and in vivo; however, most suffer from cytotoxicity due in part to a lack of selectivity for endosomal versus cell membrane lysis. For polymer based carriers to move beyond the laboratory and into the clinic, it is critical to find carriers that are not only efficacious, but also have margins that are clinically relevant. In this paper we report three distinct categories of polymer conjugates that improve the selectivity of endosomal membrane lysis by relying on the change in pH associated with endosomal trafficking, including incorporation of low pKa heterocycles, acid cleavable amino side chains, or carboxylic acid pH sensitive charge switches. Additionally, we determine the therapeutic index of our polymer conjugates in vivo and demonstrate that the incorporation of pH responsive elements dramatically expands the therapeutic index to 10-15, beyond that of the therapeutic index (less than 3), for polymer conjugates previously reported.


Asunto(s)
Concentración de Iones de Hidrógeno , Polímeros/uso terapéutico , ARN Interferente Pequeño/uso terapéutico , Animales , Polímeros/química , Polímeros/farmacocinética , ARN Interferente Pequeño/química , ARN Interferente Pequeño/farmacocinética , Ratas
9.
Bioorg Med Chem Lett ; 24(12): 2737-40, 2014 Jun 15.
Artículo en Inglés | MEDLINE | ID: mdl-24813734

RESUMEN

Elevated plasma homocysteine (Hcy) levels are an independent risk factor for the onset and progression of Alzheimer's disease. Reduction of Hcy to normal levels therefore presents a new approach for disease modification. Hcy is produced by the cytosolic enzyme S-adenosylhomocysteine hydrolase (AHCY), which converts S-adenosylhomocysteine (SAH) to Hcy and adenosine. Herein we describe the design and characterization of novel, substrate-based S-adenosylhomocysteine hydrolase inhibitors with low nanomolar potency in vitro and robust activity in vivo.


Asunto(s)
Adenosina/análogos & derivados , Diseño de Fármacos , Hidrolasas/antagonistas & inhibidores , S-Adenosilhomocisteína , Adenosina/química , Adenosina/farmacología , Animales , Química Encefálica , Activación Enzimática/efectos de los fármacos , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/farmacología , Homocisteína/sangre , Enlace de Hidrógeno , Concentración 50 Inhibidora , Modelos Moleculares , Ratas , S-Adenosilhomocisteína/química , Especificidad por Sustrato
10.
Nat Commun ; 15(1): 489, 2024 Jan 12.
Artículo en Inglés | MEDLINE | ID: mdl-38216578

RESUMEN

Although stapled α-helical peptides can address challenging targets, their advancement is impeded by poor understandings for making them cell permeable while avoiding off-target toxicities. By synthesizing >350 molecules, we present workflows for identifying stapled peptides against Mdm2(X) with in vivo activity and no off-target effects. Key insights include a clear correlation between lipophilicity and permeability, removal of positive charge to avoid off-target toxicities, judicious anionic residue placement to enhance solubility/behavior, optimization of C-terminal length/helicity to enhance potency, and optimization of staple type/number to avoid polypharmacology. Workflow application gives peptides with >292x improved cell proliferation potencies and no off-target cell proliferation effects ( > 3800x on-target index). Application of these 'design rules' to a distinct Mdm2(X) peptide series improves ( > 150x) cellular potencies and removes off-target toxicities. The outlined workflow should facilitate therapeutic impacts, especially for those targets such as Mdm2(X) that have hydrophobic interfaces and are targetable with a helical motif.


Asunto(s)
Péptidos , Proteínas Proto-Oncogénicas c-mdm2 , Péptidos/farmacología , Péptidos/química
11.
Bioconjug Chem ; 24(4): 640-7, 2013 Apr 17.
Artículo en Inglés | MEDLINE | ID: mdl-23496378

RESUMEN

Efficient siRNA delivery is dependent not only on the ability of the delivery vehicle to target a specific organ but also on its ability to enable siRNA entry into the cytoplasm of the target cells. Polymers with endosomolytic properties are increasingly being used as siRNA delivery vehicles due to their potential to facilitate endosomal escape and intracellular delivery. Addition of disulfide bonds in the backbone of these polymers was expected to provide degradability through reduction by glutathione in cytosol. This paper describes the synthesis of new endosomolytic bioreducible poly(amido amine disulfide) polymers whose lytic potential can be masked at physiological pH, but can be restored at acidic endosomal pH. These polymer conjugates gave good in vitro knockdown (KD) and did not demonstrate cytotoxicity in a MTS assay. Efficient mRNA KD for apolipoprotein B in mouse liver was observed with these polyconjugates following intravenous dosing.


Asunto(s)
Disulfuros/química , Sistemas de Liberación de Medicamentos , Endosomas/metabolismo , Poliaminas/química , ARN Interferente Pequeño/administración & dosificación , Animales , Apolipoproteínas B/deficiencia , Apolipoproteínas B/genética , Eritrocitos/efectos de los fármacos , Silenciador del Gen/efectos de los fármacos , Hemólisis/efectos de los fármacos , Células Hep G2 , Humanos , Hígado/efectos de los fármacos , Hígado/metabolismo , Ratones , Estructura Molecular , Oxidación-Reducción , ARN Mensajero/efectos de los fármacos , ARN Mensajero/genética , ARN Interferente Pequeño/farmacología
12.
J Med Chem ; 65(7): 5593-5605, 2022 04 14.
Artículo en Inglés | MEDLINE | ID: mdl-35298158

RESUMEN

We have identified a series of novel insulin receptor partial agonists (IRPAs) with a potential to mitigate the risk of hypoglycemia associated with the use of insulin as an antidiabetic treatment. These molecules were designed as dimers of native insulin connected via chemical linkers of variable lengths with optional capping groups at the N-terminals of insulin chains. Depending on the structure, the maximal activation level (%Max) varied in the range of ∼20-70% of native insulin, and EC50 values remained in sub-nM range. Studies in minipig and dog demonstrated that IRPAs had sufficient efficacy to normalize plasma glucose levels in diabetes, while providing reduction of hypoglycemia risk. IRPAs had a prolonged duration of action, potentially making them suitable for once-daily dosing. Two lead compounds with %Max values of 30 and 40% relative to native insulin were selected for follow up studies in the clinic.


Asunto(s)
Diabetes Mellitus Tipo 2 , Hipoglucemia , Animales , Glucemia , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Perros , Hipoglucemia/tratamiento farmacológico , Hipoglucemiantes/farmacología , Hipoglucemiantes/uso terapéutico , Insulina/uso terapéutico , Receptor de Insulina , Porcinos , Porcinos Enanos , Índice Terapéutico
13.
Bioorg Med Chem Lett ; 25(21): 4714, 2015 Nov 01.
Artículo en Inglés | MEDLINE | ID: mdl-26358161
14.
Bioorg Med Chem Lett ; 20(10): 3129-33, 2010 May 15.
Artículo en Inglés | MEDLINE | ID: mdl-20409708

RESUMEN

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.


Asunto(s)
Oxazolidinonas/química , Receptores de Glutamato Metabotrópico/metabolismo , Esquizofrenia/tratamiento farmacológico , Regulación Alostérica , Animales , Antipsicóticos , Ketamina/toxicidad , Oxazolidinonas/síntesis química , Oxazolidinonas/farmacología , Ratas , Receptores de Glutamato Metabotrópico/agonistas , Relación Estructura-Actividad
15.
Bioorg Med Chem Lett ; 19(4): 1240-4, 2009 Feb 15.
Artículo en Inglés | MEDLINE | ID: mdl-19155174

RESUMEN

A high throughput screening campaign was designed to identify allosteric inhibitors of Chk1 kinase by testing compounds at high concentration. Activity was then observed at K(m) for ATP and at near-physiological concentrations of ATP. This strategy led to the discovery of a non-ATP competitive thioquinazolinone series which was optimized for potency and stability. An X-ray crystal structure for the complex of our best inhibitor bound to Chk1 was solved, indicating that it binds to an allosteric site approximately 13A from the ATP binding site. Preliminary data is presented for several of these compounds.


Asunto(s)
Inhibidores de Proteínas Quinasas/síntesis química , Inhibidores de Proteínas Quinasas/farmacología , Proteínas Quinasas/efectos de los fármacos , Quinazolinas/síntesis química , Quinazolinas/farmacología , Sitios de Unión , Quinasa 1 Reguladora del Ciclo Celular (Checkpoint 1) , Técnicas Químicas Combinatorias , Cristalografía por Rayos X , Humanos , Conformación Molecular , Estructura Molecular , Inhibidores de Proteínas Quinasas/química , Proteínas Quinasas/química , Proteínas Quinasas/metabolismo , Quinazolinas/química
16.
Science ; 363(6424)2019 Jan 18.
Artículo en Inglés | MEDLINE | ID: mdl-30655413

RESUMEN

Innovations in synthetic chemistry have enabled the discovery of many breakthrough therapies that have improved human health over the past century. In the face of increasing challenges in the pharmaceutical sector, continued innovation in chemistry is required to drive the discovery of the next wave of medicines. Novel synthetic methods not only unlock access to previously unattainable chemical matter, but also inspire new concepts as to how we design and build chemical matter. We identify some of the most important recent advances in synthetic chemistry as well as opportunities at the interface with partner disciplines that are poised to transform the practice of drug discovery and development.


Asunto(s)
Química Farmacéutica/tendencias , Descubrimiento de Drogas , Preparaciones Farmacéuticas/síntesis química , Biocatálisis , Industria Farmacéutica , Enzimas/química , Ensayos Analíticos de Alto Rendimiento , Invenciones , Aprendizaje Automático , Fotoquímica
17.
Arch Biochem Biophys ; 469(2): 220-31, 2008 Jan 15.
Artículo en Inglés | MEDLINE | ID: mdl-17999913

RESUMEN

The kinesin spindle protein (KSP, also known as Eg5) is essential for the proper separation of spindle poles during mitosis, and inhibition results in mitotic arrest and the formation of characteristic monoaster spindles. Several distinct classes of KSP inhibitors have been described previously in the public and patent literature. However, most appear to share a common induced-fit allosteric binding site, suggesting a common mechanism of inhibition. In a high-throughput screen for inhibitors of KSP, a novel class of thiazole-containing inhibitors was identified. Unlike the previously described allosteric KSP inhibitors, the thiazoles described here show ATP competitive kinetic behavior, consistent with binding within the nucleotide binding pocket. Although they bind to a pocket that is highly conserved across kinesins, these molecules exhibit significant selectivity for KSP over other kinesins and other ATP-utilizing enzymes. Several of these compounds are active in cells and produce a phenotype similar to that observed with previously published allosteric inhibitors of KSP.


Asunto(s)
Adenosina Trifosfato/metabolismo , Bioquímica/métodos , Cinesinas/antagonistas & inhibidores , Cinesinas/química , Mitosis , Adenosina Trifosfato/química , Sitio Alostérico , Unión Competitiva , Diseño de Fármacos , Humanos , Cinesinas/metabolismo , Modelos Biológicos , Modelos Químicos , Nucleótidos/química , Fenotipo , Unión Proteica , Tiazoles/farmacología
19.
Cell Chem Biol ; 23(1): 10-17, 2016 Jan 21.
Artículo en Inglés | MEDLINE | ID: mdl-26933732

RESUMEN

Chemical probes represent an important component of both academic and pharmaceutical drug discovery research. As a complement to prior reviews that have defined this scientific field, we aim to provide an industry perspective on the value of having high-quality chemical probes throughout the course of preclinical research. By studying examples from the internal Merck pipeline, we recognize that these probes require significant collaborative investment to realize their potential impact in clarifying the tractability and translation of a given therapeutic target. This perspective concludes with recommendations for chemical probe discovery aimed toward maximizing their potential to identify targets that result in the successful delivery of novel therapeutics.


Asunto(s)
Descubrimiento de Drogas/métodos , Proteínas/metabolismo , Bibliotecas de Moléculas Pequeñas/química , Bibliotecas de Moléculas Pequeñas/farmacología , Animales , Dipeptidil Peptidasa 4/metabolismo , Inhibidores de la Dipeptidil-Peptidasa IV/química , Inhibidores de la Dipeptidil-Peptidasa IV/farmacología , Inhibidores de Integrasa VIH/química , Inhibidores de Integrasa VIH/farmacología , Humanos , Proteína 2 Quinasa Serina-Treonina Rica en Repeticiones de Leucina , Terapia Molecular Dirigida , Biosíntesis de Proteínas/efectos de los fármacos , Proteínas Serina-Treonina Quinasas/antagonistas & inhibidores , Proteínas Serina-Treonina Quinasas/metabolismo , Proteínas/agonistas , Proteínas/antagonistas & inhibidores , Proteínas Proto-Oncogénicas c-akt/antagonistas & inhibidores , Proteínas Proto-Oncogénicas c-akt/metabolismo , Receptor Cannabinoide CB2/agonistas , Receptor Cannabinoide CB2/metabolismo
20.
ACS Med Chem Lett ; 7(3): 312-7, 2016 Mar 10.
Artículo en Inglés | MEDLINE | ID: mdl-26985321

RESUMEN

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.

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