RESUMEN
We have discovered a novel series of isothiazole-based phenylpropanoic acids as GPR120 agonists. Extensive structure-activity relationship studies led to the discovery of a potent GPR120 agonist 4x, which displayed good EC50 values in both calcium and ß-arrestin assays. It also presented good pharmaceutical properties and a favorable PK profile. Moreover, it demonstrated in vivo antidiabetic activity in C57BL/6 DIO mice. Studies in WT and knockout DIO mice showed that it improved glucose handling during an OGTT via GPR120. Overall, 4x possessed promising antidiabetic effect and good safety profile to be a development candidate.
RESUMEN
A novel series of 5-membered heterocycle-containing phenylpropanoic acid derivatives was discovered as potent GPR120 agonists with low clearance, high oral bioavailability and in vivo antidiabetic activity in rodents.
Asunto(s)
Hipoglucemiantes/química , Hipoglucemiantes/farmacología , Fenilpropionatos/química , Fenilpropionatos/farmacología , Receptores Acoplados a Proteínas G/agonistas , Animales , Disponibilidad Biológica , Glucemia/análisis , Glucemia/metabolismo , Diabetes Mellitus Tipo 2/sangre , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Diabetes Mellitus Tipo 2/metabolismo , Diseño de Fármacos , Células HEK293 , Compuestos Heterocíclicos/química , Compuestos Heterocíclicos/farmacocinética , Compuestos Heterocíclicos/farmacología , Compuestos Heterocíclicos/uso terapéutico , Humanos , Hipoglucemiantes/farmacocinética , Hipoglucemiantes/uso terapéutico , Ratones Endogámicos C57BL , Fenilpropionatos/farmacocinética , Fenilpropionatos/uso terapéutico , Receptores Acoplados a Proteínas G/metabolismo , Relación Estructura-ActividadRESUMEN
SAR study of 5-aminooctahydrocyclopentapyrrole-3a-carboxamide scaffold led to identification of several CCR2 antagonists with potent activity in both binding and functional assays. Their cardiovascular safety and pharmacokinetic properties were also evaluated.
Asunto(s)
Ciclopentanos/farmacología , Descubrimiento de Drogas , Pirroles/farmacología , Receptores CCR2/antagonistas & inhibidores , Ciclopentanos/síntesis química , Ciclopentanos/química , Relación Dosis-Respuesta a Droga , Humanos , Conformación Molecular , Pirroles/síntesis química , Pirroles/química , Relación Estructura-ActividadRESUMEN
Novel CCR2 antagonists with a novel 2-aminooctahydrocyclopentalene-3a-carboxamide scaffold were designed. SAR studies led to a series of potent compounds. For example, compound 51 had a good PK profile in both dog and monkey, and exhibited excellent efficacy when dosed orally in an inflammation model in hCCR2 KI mice. In addition, an asymmetric synthesis to the core structures was developed.
Asunto(s)
Amidas/química , Compuestos Bicíclicos Heterocíclicos con Puentes/química , Ciclopentanos/química , Piridinas/química , Receptores CCR2/antagonistas & inhibidores , Administración Oral , Amidas/farmacocinética , Amidas/uso terapéutico , Animales , Compuestos Bicíclicos Heterocíclicos con Puentes/farmacocinética , Compuestos Bicíclicos Heterocíclicos con Puentes/uso terapéutico , Modelos Animales de Enfermedad , Perros , Semivida , Haplorrinos , Humanos , Inflamación/tratamiento farmacológico , Ratones , Ratones Noqueados , Unión Proteica , Piridinas/farmacocinética , Piridinas/uso terapéutico , Receptores CCR2/genética , Receptores CCR2/metabolismo , Estereoisomerismo , Relación Estructura-ActividadRESUMEN
A small set of acyclic analogs 5 were prepared to explore their structure-activity relationships (SARs) relative to heterocyclic core, opioid receptor (OR) agonists 4. Compound 5l was found to have very favorable OR binding affinities at the δ and µ ORs (r K(i) δ=1.3 nM; r K(i) µ=0.9 nM; h K(i) µ=1.7 nM), with less affinity for the κ OR (gp K(i) κ=55 nM). The OR functional profile for 5l varied from the previously described dual δ/µ OR agonists 4, with 5l being a potent, mixed dual δ OR antagonist/µ OR agonist [δ IC(50)=89 nM (HVD); µ EC(50)=1 nM (GPI); κ EC(50)=1.6 µM (GPC)]. Compound 5l has progressed through a clinical Phase II Proof of Concept study on 800 patients suffering from diarrhea-predominant Irritable Bowel Syndrome (IBS-d). This Phase II study was recently completed successfully, with 5l demonstrating statistically significant efficacy over placebo.
Asunto(s)
Diarrea/etiología , Síndrome del Colon Irritable/tratamiento farmacológico , Receptores Opioides delta/antagonistas & inhibidores , Receptores Opioides mu/agonistas , Ensayos Clínicos Fase II como Asunto , Humanos , Síndrome del Colon Irritable/complicaciones , Estructura Molecular , Relación Estructura-ActividadRESUMEN
A series of 4-azetidinyl-1-aryl-cyclohexanes as potent CCR2 antagonists with high selectivity over activity for the hERG potassium channel is discovered through divergent SARs of CCR2 and hERG.
Asunto(s)
Azetidinas/farmacología , Descubrimiento de Drogas , Canales de Potasio Éter-A-Go-Go/antagonistas & inhibidores , Hipuratos/farmacología , Receptores CCR2/antagonistas & inhibidores , Azetidinas/síntesis química , Azetidinas/química , Relación Dosis-Respuesta a Droga , Canales de Potasio Éter-A-Go-Go/metabolismo , Hipuratos/síntesis química , Hipuratos/química , Humanos , Estructura Molecular , Receptores CCR2/metabolismo , Estereoisomerismo , Relación Estructura-ActividadRESUMEN
The unexpected observation of a hyperglycemic effect of some tricycle-based delta opioid receptor (DOR) agonists led to a series of studies to better understand the finding. Single administration of two novel tricyclic DOR agonists dose dependently elevated rat plasma glucose levels; 4-week toxicology studies confirmed the hyperglycemic finding and further revealed pancreatic ß-cell hypertrophy, including vacuole formation, as well as bone dysplasia and Harderian gland degeneration with regeneration. Similar diabetogenic effects were observed in dog. A review of the literature on the antiserotonergic and antihistaminergic drug cyproheptadine (CPH) and its metabolites revealed shared structural features as well as similar hyperglycemic effects to the present series of DOR agonists. To further evaluate these effects, we established an assay measuring insulin levels in the rat pancreatic ß-cell-derived RINm5F cell line, extensively used to study CPH and its metabolites. Like CPH, the initial DOR agonists studied reduced RINm5F cell insulin levels in a concentration-dependent manner. Importantly, compound DOR potency did not correlate with the insulin-reducing potency. Furthermore, the RINm5F cell insulin results correlated with the diabetogenic effect of the compounds in a 5-day mouse study. The RINm5F cell insulin assay enabled the identification of aryl-aryl-amine DOR agonists that lacked an insulin-reducing effect and did not elevate blood glucose in repeated dosing studies conducted over a suprapharmacologic dose range. Thus, not only did the RINm5F cell assay open a path for the further discovery of DOR agonists lacking diabetogenic potential but also it established a reliable, economical, and high-throughput screen for such potential, regardless of chemotype or target pharmacology. The present findings also suggest a mechanistic link between the toxicity observed here and that underlying Wolcott-Rallison Syndrome.
Asunto(s)
Ciproheptadina/toxicidad , Hiperglucemia/inducido químicamente , Células Secretoras de Insulina/efectos de los fármacos , Antagonistas de Narcóticos/toxicidad , Páncreas/efectos de los fármacos , Antagonistas de la Serotonina/toxicidad , Animales , Glucemia/análisis , Glucemia/efectos de los fármacos , Aumento de la Célula/efectos de los fármacos , Línea Celular Tumoral , Ciproheptadina/análogos & derivados , Diabetes Mellitus Tipo 1/metabolismo , Perros , Epífisis/anomalías , Epífisis/metabolismo , Femenino , Ensayos Analíticos de Alto Rendimiento , Hiperglucemia/metabolismo , Insulina/sangre , Células Secretoras de Insulina/metabolismo , Células Secretoras de Insulina/patología , Insulinoma/tratamiento farmacológico , Insulinoma/metabolismo , Masculino , Ratones , Osteocondrodisplasias/metabolismo , Páncreas/metabolismo , Páncreas/patología , Ratas , Ratas Sprague-Dawley , Vacuolas/efectos de los fármacos , Vacuolas/ultraestructuraRESUMEN
The first chemoselective direct dehydrative cross-coupling of tautomerizable heterocycles with alkynes has been achieved via C-H/C-OH bond activations with direct C(sp(2))-C(sp) bond formation, which is in line with ideal synthesis using readily available materials.
Asunto(s)
Alquinos/química , Compuestos Heterocíclicos/química , Compuestos Organofosforados/química , Catálisis , Cobre/química , Paladio/químicaRESUMEN
Discovered as part of an effort to identify delta opioid (DOPr or DOR) agonist analgesics, JNJ-20788560 and JNJ-39204880 exhibited high DOR affinity, with K(i) values of 1.7 and 2.0nM, respectively, and were selective for DOR over the mu opioid receptor (MOPr or MOR), with 596- and 122-fold selectivity, respectively. Both compounds stimulated DOR but not MOR induced GTPgammaS binding and were effective antihyperalgesic agents in the complete Freund's adjuvant model of thermal hyperalgesia in the rat, with oral ED(50) values of 13.5 and 35mg/kg, corresponding to plasma levels of 1 and 9microM, respectively. Autoradiographic analysis of DOR and MOR occupancy in sections of brain (striatum) and lumbar spinal cord (L4-L6) was determined ex vivo, using radiolabeled naltrindole or DAMGO. Quantitative image analysis resulted in striatal DOR ED(50) values of 6.9 and 10.7mg/kg, for JNJ-20788560 and JNJ-39204880 respectively, and spinal cord values of 6.4 and 3.2mg/kg, respectively. Neither compound dose-dependently occupied MOR within the dose range studied. Thus, this study confirmed the DOR selectively over MOR of both compounds following their oral administration, and further demonstrated dose-dependent DOR occupancy by each compound across its antihyperalgesic dose range. Importantly, these in vitro, in vivo, and ex vivo data revealed that the greater in vitro potency of JNJ-20788560 was paralleled by its greater in vivo potency, although JNJ-39204880 achieved higher plasma levels following its oral administration. The receptor occupancy levels observed at the pharmacologic ED(50) doses of these compounds suggest the need for greater target engagement by JNJ-39204880 than by JNJ-20788560 to elicit a similar therapeutic response.
Asunto(s)
Analgésicos Opioides/farmacología , Autorradiografía/métodos , Compuestos de Azabiciclo/farmacología , Pirimidinas/farmacología , Pirrolidinas/farmacología , Receptores Opioides delta/agonistas , Xantenos/farmacología , Analgésicos Opioides/sangre , Animales , Compuestos de Azabiciclo/sangre , Cuerpo Estriado/diagnóstico por imagen , Cuerpo Estriado/metabolismo , Relación Dosis-Respuesta a Droga , Encefalina Ala(2)-MeFe(4)-Gli(5)/análisis , Guanosina 5'-O-(3-Tiotrifosfato)/metabolismo , Vértebras Lumbares/diagnóstico por imagen , Masculino , Naltrexona/análogos & derivados , Naltrexona/análisis , Dimensión del Dolor/efectos de los fármacos , Pirimidinas/sangre , Pirrolidinas/sangre , Radiografía , Ensayo de Unión Radioligante/métodos , Ratas , Ratas Sprague-Dawley , Ratas Wistar , Receptores Opioides delta/metabolismo , Receptores Opioides mu/efectos de los fármacos , Receptores Opioides mu/metabolismo , Médula Espinal/diagnóstico por imagen , Médula Espinal/metabolismo , Xantenos/sangreRESUMEN
Using previously reported opioid receptor (OR) agonist analogs 4a-c as starting points, the structure-activity relationship (SAR) for their related series has been further refined. This SAR study has led to the identification of 2,6-di-Me-Tyr (DMT) analogs 4h and 4j as the most potent OR agonist within the series. In addition, it was discovered that 4-(aminocarbonyl)-2,6-dimethyl-Phe is a reasonable bioisostere surrogate for the DMT moiety, as supported by the OR activities of compounds 4x and 4y.
Asunto(s)
Imidazoles/farmacología , Receptores Opioides/agonistas , Imidazoles/síntesis química , Imidazoles/química , Estructura Molecular , Estereoisomerismo , Relación Estructura-ActividadRESUMEN
This paper describes a systematic study of addition reactions between the chiral Ni(II) complex of the Schiff base of glycine with (S)-o-[N-(N-benzylprolyl)amino]benzophenone and (S)- or (R)-3-[(E)-enoyl]-4-phenyl-1,3-oxazolidin-2-ones as a general and synthetically efficient approach to beta-substituted pyroglutamic acids and relevant compounds. These reactions were shown to occur at room temperature in the presence of nonchelating organic bases and, most notably, with very high (>98% diastereomeric excess (de)) stereoselectivity at both newly formed stereogenic centers. The stereochemical outcome of the reactions was found to be overwhelmingly controlled by the stereochemical preferences of the Michael acceptors, and the chirality of the glycine complex influenced only the reaction rate. Thus, in the reactions of both the (S)-configured Ni(II) complex and the Michael acceptors, the reaction rates were exceptionally high, allowing preparation of the corresponding products with virtually quantitative (>98%) chemical and stereochemical yields. In contrast, reactions of the (S)-configured Ni(II) complex and (R)-configured Michael acceptors proceeded at noticeably lower rates, but the addition products were obtained in high diastereo- and enantiomeric purity. To rationalize the remarkably high and robust stereoselectivity observed in these reactions, we consider an enzyme-substrate-like mode of interaction involving a topographical match or mismatch of two geometric figures. Excellent chemical and stereochemical yields, combined with the simplicity and operational convenience of the experimental procedures, render the present method of immediate use for preparing various beta-substituted pyroglutamic acids and related compounds.
Asunto(s)
Glicina/química , Níquel/química , Oxazolidinonas/química , Ácido Pirrolidona Carboxílico/química , Catálisis , Cinética , Modelos Químicos , Estructura Molecular , Bases de Schiff/química , Espectrometría de Masa Bombardeada por Átomos Veloces , EstereoisomerismoRESUMEN
This study demonstrates a new strategy for controlling the stereochemical outcome of the Michael addition reactions between nucleophilic glycine equivalents and alpha,beta-unsaturated carboxylic acid derivatives: The addition reactions between achiral Ni(II)-complex of the Schiff base of glycine with o-[N-alpha-pycolylamino]acetophenone and (S)- or (R)-3-(E-enoyl)-4-phenyl-1,3-oxazolidin-2-ones were shown to occur at room temperature in the presence of nonchelating organic bases and, most notably, with very high stereoselectivity at both newly formed stereogenic centers. Thus, the chiral 4-phenyl-1,3-oxazolidin-2-one moiety was found to control efficiently both face diastereoselectivities of the glycine derived enolate and the C,C double bond of the Michael acceptor. The new strategy developed in this work is methodologically superior to previous methods, most notably in terms of generality and synthetic efficiency. Excellent chemical yields and diastereoselectivities, combined with the simplicity of the experimental procedures, render the present method of immediate use for preparing various 3-substituted pyroglutamic acids and related amino acids (glutamic acids, glutamines, prolines, etc.) available via conventional transformations of the former.
Asunto(s)
Glicina/química , Prolina/síntesis química , Ácido Pirrolidona Carboxílico/síntesis química , Estructura Molecular , Prolina/química , Ácido Pirrolidona Carboxílico/química , EstereoisomerismoRESUMEN
A stereoselective method has been developed for the synthesis of 7- and 8-substituted dipeptide beta-turn mimetic azabicyclo[4.3.0]nonane amino acid esters. The allyl groups were introduced in high diastereoselectivity, controlled by 3-phenyl or 4-benzyl groups in pyroglutamic acid derivatives 3 or 9, respectively. The precursors, dehydroamino acids 7 and 13 derived from 5 or 11, underwent asymmetric hydrogenations with Burk's DuPHOS Rh(I)-based catalysts to furnish alpha-amino acid derivatives in high stereoselectivity. The resulting amino acids 8 and 14 were converted to the beta-turn mimetics 6,5-bicyclic lactams 1a-d in high yields.
Asunto(s)
Aminoácidos/química , Compuestos Aza/síntesis química , Compuestos Bicíclicos con Puentes/síntesis química , Técnicas Químicas Combinatorias , Péptidos/síntesis química , Catálisis , Ciclización , Ésteres , Indicadores y Reactivos , Imitación Molecular , Estructura Molecular , Conformación Proteica , Estereoisomerismo , Relación Estructura-ActividadRESUMEN
The asymmetric synthesis of beta-phenyl-substituted cysteine, tryptophan, and serine derivatives was successfully developed. In this approach, the key intermediate, enantiomerically pure 3-phenylaziridine-2-carboxylic ester 7, was prepared from alpha,beta-unsaturated ester 1 by employing the Sharpless asymmetric dihydroxylation. The aziridine 7 was treated with 4-methoxybenzylthiol, indole, and acetic acid to give beta-phenyl-substituted cysteine, tryptophan, and serine, respectively, in a clean S(N)2 type ring opening at the C3 position. This general approach can be used to synthesize a variety of beta-substituted novel amino acids.