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1.
ACS Med Chem Lett ; 10(6): 941-948, 2019 Jun 13.
Artículo en Inglés | MEDLINE | ID: mdl-31223452

RESUMEN

It has been hypothesized that selective muscarinic acetylcholine receptor (mAChR) M4 subtype activation could provide therapeutic benefits to a number of neurological disorders while minimizing unwanted cholinergic side effects observed due to nonselective mAChR activation. Given the high sequence and structural homology of the orthosteric binding sites among mAChRs, achieving M4 subtype-selective activation has been challenging. Herein, we describe the discovery of a series of M4 subtype-selective agonists bearing novel carbamate isosteres. Comparison of the isosteres' electrostatic potential isosurface sheds light on key structural features for M4 subtype-selective activation. The identified key features were further illustrated in a proposed receptor-agonist interaction mode.

2.
Bioorg Med Chem Lett ; 28(3): 415-419, 2018 02 01.
Artículo en Inglés | MEDLINE | ID: mdl-29273395

RESUMEN

Oxytocin (OT) is a peptide hormone agonist of the oxytocin receptor (OTR) that has been proposed as a therapeutic to treat a number of social and emotional disorders in addition to its current clinical use to induce labor and treat postpartum bleeding. OT is administered intravenously and intranasally rather than orally, in part because its low passive permeability causes low oral bioavailability. Non-peptidic OTR agonists have also been reported, but none with the exquisite potency of the peptide based agonists. In this report, we describe the OTR agonist activity and exposed polarity of a set of truncated OT analogs as well as hybrid peptide-small molecule analogs of OT. Examples of both truncated analogs and peptide-small molecule hybrid analogs are potent and selective OTR agonists. Hybrid agonist 13, which is 232 Da smaller than OT, still retains subnanomolar potency, full agonist activity, and selectivity over V1a. While these compounds were designed to address the low permeability of OT and other full length analogs, we found that reduction in molecular weight and the removal or replacement of the three amino acid tail of OT did not have a significant effect on passive permeability.


Asunto(s)
Oxitocina/farmacología , Péptidos/farmacología , Receptores de Oxitocina/agonistas , Bibliotecas de Moléculas Pequeñas/farmacología , Relación Dosis-Respuesta a Droga , Humanos , Estructura Molecular , Peso Molecular , Oxitocina/química , Péptidos/química , Bibliotecas de Moléculas Pequeñas/química , Relación Estructura-Actividad
3.
Org Biomol Chem ; 15(12): 2501-2506, 2017 Mar 28.
Artículo en Inglés | MEDLINE | ID: mdl-28266673

RESUMEN

The synthesis and in vivo pharmacokinetic profile of an analogue of cyclosporine is disclosed. An acyclic congener was also profiled in in vitro assays to compare cell permeability. The compounds possess similar calculated and measured molecular descriptors however have different behaviors in an RRCK assay to assess cell permeability.


Asunto(s)
Ciclosporina/farmacocinética , Oligopéptidos/farmacocinética , Animales , Ciclosporina/administración & dosificación , Ciclosporina/química , Masculino , Conformación Molecular , Oligopéptidos/administración & dosificación , Oligopéptidos/química , Ratas , Ratas Wistar , Estereoisomerismo
4.
Bioorg Med Chem ; 24(16): 3513-20, 2016 08 15.
Artículo en Inglés | MEDLINE | ID: mdl-27297999

RESUMEN

Oxytocin (OT) is a peptide hormone agonist of the OT receptor (OTR) that plays an important role in social behaviors such as pair bonding, maternal bonding and trust. The pharmaceutical development of OT as an oral peptide therapeutic has been hindered historically by its unfavorable physicochemical properties, including molecular weight, polarity and number of hydrogen bond donors, which determines poor cell permeability. Here we describe the first systematic study of single and multiple N-methylations of OT and their effect on physicochemical properties as well as potency at the OT receptor. The agonist EC50 and percent effect for OTR are reported and show that most N-methylations are tolerated but with some loss in potency compared to OT. The effect of N-methylation on exposed polarity is assessed through the EPSA chromatographic method and the results validated against NMR temperature coefficient experiments and the determination of NMR solution structures. We found that backbone methylation of residues not involved in IMHB and removal of the N-terminal amine can significantly reduce the exposed polarity of peptides, and yet retain a significant OTR agonist activity. The results of this study also expose the potential challenge of using the N-methylation strategy for the OT system; while exposed polarity is reduced, in some cases backbone methylation produces a significant conformational change that compromises agonist activity. The data presented provides useful insights on the SAR of OT and suggests future design strategies that can be used to develop more permeable OTR agonists based on the OT framework.


Asunto(s)
Oxitocina/química , Enlace de Hidrógeno , Espectroscopía de Resonancia Magnética , Metilación , Relación Estructura-Actividad , Temperatura
5.
J Pharmacol Exp Ther ; 358(2): 164-72, 2016 08.
Artículo en Inglés | MEDLINE | ID: mdl-27217590

RESUMEN

Oxytocin (OT) modulates the expression of social and emotional behaviors and consequently has been proposed as a pharmacologic treatment of psychiatric diseases, including autism spectrum disorders and schizophrenia; however, endogenous OT has a short half-life in plasma and poor permeability across the blood-brain barrier. Recent efforts have focused on the development of novel drug delivery methods to enhance brain penetration, but few efforts have aimed at improving its half-life. To explore the behavioral efficacy of an OT analog with enhanced plasma stability, we developed PF-06655075 (PF1), a novel non-brain-penetrant OT receptor agonist with increased selectivity for the OT receptor and significantly increased pharmacokinetic stability. PF-06478939 was generated with only increased stability to disambiguate changes to selectivity versus stability. The efficacy of these compounds in evoking behavioral effects was tested in a conditioned fear paradigm. Both central and peripheral administration of PF1 inhibited freezing in response to a conditioned fear stimulus. Peripheral administration of PF1 resulted in a sustained level of plasma concentrations for greater than 20 hours but no detectable accumulation in brain tissue, suggesting that plasma or cerebrospinal fluid exposure was sufficient to evoke behavioral effects. Behavioral efficacy of peripherally administered OT receptor agonists on conditioned fear response opens the door to potential peripheral mechanisms in other behavioral paradigms, whether they are mediated by direct peripheral activation or feed-forward responses. Compound PF1 is freely available as a tool compound to further explore the role of peripheral OT in behavioral response.


Asunto(s)
Condicionamiento Psicológico/efectos de los fármacos , Descubrimiento de Drogas , Miedo/psicología , Pérdida de Tono Postural/efectos de los fármacos , Oxitocina/administración & dosificación , Oxitocina/farmacología , Péptidos Cíclicos/administración & dosificación , Péptidos Cíclicos/farmacología , Polietilenglicoles/administración & dosificación , Polietilenglicoles/farmacología , Receptores de Oxitocina/agonistas , Animales , Células CHO , Cricetinae , Cricetulus , Vías de Administración de Medicamentos , Pérdida de Tono Postural/fisiología , Masculino , Ratones , Oxitocina/química , Oxitocina/farmacocinética , Péptidos Cíclicos/química , Péptidos Cíclicos/farmacocinética , Polietilenglicoles/química , Polietilenglicoles/farmacocinética , Ratas
6.
Bioorg Med Chem Lett ; 23(4): 1120-6, 2013 Feb 15.
Artículo en Inglés | MEDLINE | ID: mdl-23298810

RESUMEN

Microsomal prostaglandin E(2) synthase-1 (mPGES-1) is a novel therapeutic target for the treatment of inflammation and pain. In the preceding letter, we detailed the discovery of clinical candidate PF-04693627, a potent mPGES-1 inhibitor possessing a novel benzoxazole structure. While PF-04693627 was undergoing further preclinical profiling, we sought to identify a back-up mPGES-1 inhibitor that differentiated itself from PF-04693627. The design, synthesis, mPGES-1 activity and in vivo PK of a novel set of substituted benzoxazoles are described herein. Also described is a conformation-based hypothesis for mPGES-1 activity based on the preferred conformation of the cyclohexane ring within this class of inhibitors.


Asunto(s)
Benzoxazoles/química , Benzoxazoles/farmacología , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/farmacología , Oxidorreductasas Intramoleculares/antagonistas & inhibidores , Benzoxazoles/síntesis química , Diseño de Fármacos , Inhibidores Enzimáticos/síntesis química , Humanos , Oxidorreductasas Intramoleculares/química , Oxidorreductasas Intramoleculares/metabolismo , Modelos Moleculares , Conformación Molecular , Prostaglandina-E Sintasas , Relación Estructura-Actividad
7.
Bioorg Med Chem Lett ; 23(3): 907-11, 2013 Feb 01.
Artículo en Inglés | MEDLINE | ID: mdl-23266122

RESUMEN

A novel series of potent benzoxazole mPGES-1 inhibitors has been derived from a hit from a high throughput screen. Compound 37 displays mPGES-1 inhibition in an enzyme assay (0.018 µM) and PGE-2 inhibition in a cell-based assay (0.034 µM). It demonstrates 500- and 2500-fold selectivity for mPGES-1 over COX-2 and 6-keto PGF-1α, respectively. In vivo PK studies in dogs demonstrate 55% oral bioavailability and an 7 h half-life.


Asunto(s)
Benzoxazoles/química , Inhibidores Enzimáticos/química , Oxidorreductasas Intramoleculares/antagonistas & inhibidores , Amidas/síntesis química , Amidas/química , Amidas/farmacología , Animales , Benzoxazoles/síntesis química , Benzoxazoles/farmacocinética , Benzoxazoles/farmacología , Disponibilidad Biológica , Perros , Activación Enzimática/efectos de los fármacos , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/farmacología , Humanos , Concentración 50 Inhibidora , Estructura Molecular , Prostaglandina-E Sintasas , Relación Estructura-Actividad
8.
J Med Chem ; 54(24): 8490-500, 2011 Dec 22.
Artículo en Inglés | MEDLINE | ID: mdl-22040023

RESUMEN

Analogues substituted with various amines at the 6-position of the pyrazine ring on (4-amino-7-isopropyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)pyrazin-2-ylmethanone were discovered as potent and selective inhibitors of PDK1 with potential as anticancer agents. An early lead with 2-pyridine-3-ylethylamine as the pyrazine substituent showed moderate potency and selectivity. Structure-based drug design led to improved potency and selectivity against PI3Kα through a combination of cyclizing the ethylene spacer into a saturated, five-membered ring and substituting on the 4-position of the aryl ring with a fluorine. ADME properties were improved by lowering the lipophilicity with heteroatom replacements in the saturated, five-membered ring. The optimized analogues have a PDK1 Ki of 1 nM and >100-fold selectivity against PI3K/AKT-pathway kinases. The cellular potency of these analogues was assessed by the inhibition of AKT phosphorylation (T308) and by their antiproliferation activity against a number of tumor cell lines.


Asunto(s)
Antineoplásicos/síntesis química , Proteínas Serina-Treonina Quinasas/antagonistas & inhibidores , Piridinas/síntesis química , Pirroles/síntesis química , Proteínas Quinasas Dependientes de 3-Fosfoinosítido , Antineoplásicos/química , Antineoplásicos/farmacología , Línea Celular Tumoral , Cristalografía por Rayos X , Ensayos de Selección de Medicamentos Antitumorales , Etilaminas/síntesis química , Etilaminas/química , Etilaminas/farmacología , Humanos , Modelos Moleculares , Fosforilación , Conformación Proteica , Proteínas Proto-Oncogénicas c-akt/metabolismo , Piridinas/química , Piridinas/farmacología , Pirroles/química , Pirroles/farmacología , Transducción de Señal , Relación Estructura-Actividad
9.
Bioorg Med Chem Lett ; 21(2): 849-52, 2011 Jan 15.
Artículo en Inglés | MEDLINE | ID: mdl-21185721

RESUMEN

S6K1 (p70 S6 kinase-1) is thought to play a critical role in the development of obesity and insulin resistance, thus making it an attractive target in developing medicines for the treatment of these disorders. We describe a novel thiophene urea class of S6K inhibitors. The lead matter for the development of these inhibitors came from mining the literature for reports of weak off-target S6K activity. These optimized inhibitors exhibit good potency and excellent selectivity for S6K over a panel of 43 kinases.


Asunto(s)
Inhibidores de Proteínas Quinasas/química , Inhibidores de Proteínas Quinasas/farmacología , Proteínas Quinasas S6 Ribosómicas 70-kDa/antagonistas & inhibidores , Tiofenos/química , Tiofenos/farmacología , Humanos , Microsomas Hepáticos/metabolismo , Inhibidores de Proteínas Quinasas/metabolismo , Proteínas Quinasas S6 Ribosómicas 70-kDa/metabolismo , Relación Estructura-Actividad , Tiofenos/metabolismo , Urea/química , Urea/metabolismo , Urea/farmacología
10.
Bioorg Med Chem Lett ; 19(12): 3339-43, 2009 Jun 15.
Artículo en Inglés | MEDLINE | ID: mdl-19435660

RESUMEN

PC-1 (NPP-1) inhibitors may be useful as therapeutics for the treatment of CDDP (calcium pyrophosphate dehydrate) deposition disease and osteoarthritis. We have identified a series of potent quinazolin-4-piperidin-4-ethyl sulfamide PC-1 inhibitors. The series, however, suffers from high affinity binding to hERG potassium channels, which can cause drug-induced QT prolongation. We used a hERG homology model to identify potential key interactions between our compounds and hERG, and the information gained was used to design and prepare a series of quinazolin-4-piperidin-4-methyl sulfamides that retain PC-1 activity but lack binding affinity for hERG.


Asunto(s)
Piperidinas/farmacología , Pirofosfatasas/antagonistas & inhibidores , Quinazolinas/farmacología , Sulfonamidas/farmacología , Diseño de Fármacos , Inhibidores Enzimáticos/química , Canales de Potasio Éter-A-Go-Go/metabolismo , Humanos , Síndrome de QT Prolongado , Osteoartritis/tratamiento farmacológico , Hidrolasas Diéster Fosfóricas , Piperidinas/química , Unión Proteica , Quinazolinas/química , Sulfonamidas/química
11.
Biochem J ; 420(2): 283-94, 2009 May 13.
Artículo en Inglés | MEDLINE | ID: mdl-19243309

RESUMEN

JNK1 (c-Jun N-terminal kinase 1) plays a crucial role in the regulation of obesity-induced insulin resistance and is implicated in the pathology of Type 2 diabetes. Its partner, JIP1 (JNK-interacting protein 1), serves a scaffolding function that facilitates JNK1 activation by MKK4 [MAPK (mitogen-activated protein kinase) kinase 4] and MKK7 (MAPK kinase 7). For example, reduced insulin resistance and JNK activation are observed in JIP1-deficient mice. On the basis of the in vivo efficacy of a cell-permeable JIP peptide, the JIP-JNK interaction appears to be a potential target for JNK inhibition. The goal of the present study was to identify small-molecule inhibitors that disrupt the JIP-JNK interaction to provide an alternative approach for JNK inhibition to ATP-competitive inhibitors. High-throughput screening was performed by utilizing a fluorescence polarization assay that measured the binding of JNK1 to the JIP peptide. Multiple chemical series were identified, revealing two categories of JIP/JNK inhibitors: 'dual inhibitors' that are ATP competitive and probably inhibit JIP-JNK binding allosterically, and 'JIP-site binders' that block binding through interaction with the JIP site. A series of polychloropyrimidines from the second category was characterized by biochemical methods and explored through medicinal-chemistry efforts. As predicted, these inhibitors also inhibited full-length JIP-JNK binding and were selective against a panel of 34 representative kinases, including ones in the MAPK family. Overall, this work demonstrates that small molecules can inhibit protein-protein interactions in vitro in the MAPK family effectively and provides strategies for similar approaches within other target families.


Asunto(s)
Proteínas Adaptadoras Transductoras de Señales/metabolismo , Proteínas Quinasas JNK Activadas por Mitógenos/metabolismo , Compuestos Orgánicos/farmacología , Proteínas Adaptadoras Transductoras de Señales/química , Animales , Humanos , Proteínas Quinasas JNK Activadas por Mitógenos/química , Modelos Moleculares , Estructura Molecular , Compuestos Orgánicos/química , Unión Proteica/efectos de los fármacos , Estructura Terciaria de Proteína , Relación Estructura-Actividad
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