RESUMEN
We report the discovery of a series of novel zwitterionic hPTHR1 antagonists. Optimization of lead compound 2 led to 4-[[1-[4-(2,9-dichloro-5,5-dimethyl-6-oxo-pyrido[2,3-d][1]benzazepin-7-yl)phenyl]-3-fluoro-azetidin-3-yl]methylamino]cyclohexanecarboxylic acid (19e, DS69910557), a compound with excellent potency and selectivity over activity at the human ether-a-go-go-related-gene (hERG) channel. Compound 19e demonstrated in vivo potency to decrease the plasma calcium concentration in rats upon oral administration. 2022 Elsevier Ltd. All rights reserved.
Asunto(s)
Benzazepinas/farmacología , Receptor de Hormona Paratiroídea Tipo 1 , Administración Oral , Animales , Humanos , Ratas , Relación Estructura-ActividadRESUMEN
Structural modification of a 1,4-benzodiazepin-2-one-based PTHR1 antagonist 5, a novel type of PTHR1 antagonist previously synthesized in our laboratories, yielded compound 10, which had better chemical stability than compound 5. Successive optimization of the lead 10 improved aqueous solubility, metabolic stability, and animal pharmacokinetics, culminating in the identification of DS37571084 (12). Our study paves the way for the discovery of novel and orally bioavailable PTHR1 antagonists.
Asunto(s)
Descubrimiento de Drogas , Receptor de Hormona Paratiroídea Tipo 1/antagonistas & inhibidores , Administración Oral , Animales , Disponibilidad Biológica , Relación Dosis-Respuesta a Droga , Humanos , Masculino , Microsomas Hepáticos/química , Microsomas Hepáticos/metabolismo , Estructura Molecular , Ratas , Ratas Sprague-Dawley , Receptor de Hormona Paratiroídea Tipo 1/metabolismo , Relación Estructura-ActividadRESUMEN
The discovery and optimization of a novel series of PTHR1 antagonists are described. Starting from known PTHR1 antagonists, we identified more potent 1,4-benzodiazepin-2-one derivatives by means of a scaffold-hopping approach. The representative compound 23 (DS08210767) exhibited nanomolar-level PTHR1 antagonist activity and potential oral bioavailability in a pharmacokinetic study.
Asunto(s)
Benzodiazepinonas/farmacología , Descubrimiento de Drogas , Receptor de Hormona Paratiroídea Tipo 1/antagonistas & inhibidores , Benzodiazepinonas/síntesis química , Benzodiazepinonas/química , Relación Dosis-Respuesta a Droga , Humanos , Estructura Molecular , Receptor de Hormona Paratiroídea Tipo 1/metabolismo , Relación Estructura-ActividadRESUMEN
Novel compounds based on 1a were synthesized with the focus of obtaining agonists acting upon peripheral BRS-3. To identify potent anti-obesity compounds without adverse effects on the central nervous system (CNS), a carboxylic acid moiety and a labile carboxylic ester with an antedrug functionality were introduced. Through the extensive synthetic exploration and the pharmacokinetic studies of intravenous administration in mice, the ester 2b was selected owing to its most suitable pharmacological profile. In the evaluation of food intake suppression in C57BL/6N mice, 2b showed significant in vivo efficacy and no clear adverse effects on blood pressure change in dogs administered the compound by intravenous infusion.
Asunto(s)
Acetatos/química , Fármacos Antiobesidad/síntesis química , Compuestos Heterocíclicos con 2 Anillos/química , Imidazoles/química , Receptores de Bombesina/agonistas , Acetatos/metabolismo , Acetatos/farmacología , Animales , Fármacos Antiobesidad/metabolismo , Fármacos Antiobesidad/farmacología , Presión Sanguínea/efectos de los fármacos , Encéfalo/efectos de los fármacos , Encéfalo/metabolismo , Sistema Nervioso Central/efectos de los fármacos , Sistema Nervioso Central/metabolismo , Perros , Ingestión de Alimentos/efectos de los fármacos , Semivida , Frecuencia Cardíaca/efectos de los fármacos , Compuestos Heterocíclicos con 2 Anillos/metabolismo , Compuestos Heterocíclicos con 2 Anillos/farmacología , Humanos , Inyecciones Intravenosas , Ratones , Ratones Endogámicos C57BL , Receptores de Bombesina/metabolismoRESUMEN
Expansion of the 6-membered ring and subsequent fine-tuning of the newly obtained 7-membered spiropiperidine structure resulted in the discovery of a series of novel and potent SCD1 inhibitors. Preliminary SAR was explored by modifying an alkyl chain on the azepine nitrogen and resulted in the identification of a highly potent SCD1 inhibitor: 6-[5-(cyclopropylmethyl)-4,5-dihydro-1'H,3H-spiro[1,5-benzoxazepine-2,4'-piperidin]-1'-yl]-N-(2-hydroxy-2-pyridin-3-ylethyl)pyridazine-3-carboxamide (9). Compound 9 exhibited an IC(50) value of 0.01 µM against human SCD1.
Asunto(s)
Descubrimiento de Drogas , Inhibidores Enzimáticos/farmacología , Piperidinas/farmacología , Compuestos de Espiro/farmacología , Estearoil-CoA Desaturasa/antagonistas & inhibidores , Animales , Activación Enzimática/efectos de los fármacos , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/química , Células HEK293 , Humanos , Ratones , Estructura Molecular , Piperidinas/síntesis química , Piperidinas/química , Compuestos de Espiro/síntesis química , Compuestos de Espiro/química , Estearoil-CoA Desaturasa/metabolismo , Estereoisomerismo , Relación Estructura-ActividadRESUMEN
In continuation of our investigation on novel stearoyl-CoA desaturase (SCD) 1 inhibitors, we have already reported on the structural modification of the benzoylpiperidines that led to a series of novel and highly potent spiropiperidine-based SCD1 inhibitors. In this report, we would like to extend the scope of our previous investigation and disclose details of the synthesis, SAR, ADME, PK, and pharmacological evaluation of the spiropiperidines with high potency for SCD1 inhibition. Our current efforts have culminated in the identification of 5-fluoro-1'-{6-[5-(pyridin-3-ylmethyl)-1,3,4-oxadiazol-2-yl]pyridazin-3-yl}-3,4-dihydrospiro[chromene-2,4'-piperidine] (10e), which demonstrated a very strong potency for liver SCD1 inhibition (ID(50)=0.6 mg/kg). This highly efficacious inhibition is presumed to be the result of a combination of strong enzymatic inhibitory activity (IC(50) (mouse)=2 nM) and good oral bioavailability (F >95%). Pharmacological evaluation of 10e has demonstrated potent, dose-dependent reduction of the plasma desaturation index in C57BL/6J mice on a high carbohydrate diet after a 7-day oral administration (q.d.). In addition, it did not cause any noticeable skin abnormalities up to the highest dose (10 mg/kg).
Asunto(s)
Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/farmacología , Piridinas/síntesis química , Piridinas/farmacología , Estearoil-CoA Desaturasa/antagonistas & inhibidores , Animales , Evaluación Preclínica de Medicamentos , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/farmacocinética , Espectroscopía de Resonancia Magnética , Ratones , Ratones Endogámicos C57BL , Piridinas/química , Piridinas/farmacocinética , Espectrometría de Masa por Ionización de Electrospray , Relación Estructura-ActividadRESUMEN
High S(N)2' selectivity in the allylic substitution of cyclohexylidene ethyl picolinates with copper reagents prepared from RMgBr and CuBr.Me(2)S was realized by addition of ZnX(2) (X = I, Br, Cl). Furthermore, ZnX(2) accelerated the reaction with the bulky iPr reagent.
Asunto(s)
Ciclohexanos/química , Carbono/química , Cobre/química , Ácidos Picolínicos/químicaRESUMEN
Cyclization of the benzoylpiperidine in lead compound 2 generated a series of novel and highly potent spiropiperidine-based stearoyl-CoA desaturase (SCD)-1 inhibitors. Among them, 1'-{6-[5-(pyridin-3-ylmethyl)-1,3,4-oxadiazol-2-yl]pyridazin-3-yl}-5-(trifluoromethyl)-3,4-dihydrospiro[chromene-2,4'-piperidine] (19) demonstrated the most powerful inhibitory activity against SCD-1, not only in vitro but also in vivo (C57BL/6J mice). With regard to the pharmacological evaluation, 19 showed powerful reduction of the desaturation index in the plasma of C57BL/6J mice on a non-fat diet after a 7-day oral administration (q.d.) without causing notable abnormalities in the eyes or skin up to the highest dose (3mg/kg) in our preliminary analysis.
Asunto(s)
Benzopiranos/síntesis química , Piperidinas/síntesis química , Estearoil-CoA Desaturasa/antagonistas & inhibidores , Administración Oral , Animales , Benzopiranos/química , Benzopiranos/farmacocinética , Línea Celular Tumoral , Humanos , Ratones , Ratones Endogámicos C57BL , Microsomas Hepáticos/metabolismo , Piperidinas/química , Piperidinas/farmacocinética , Estearoil-CoA Desaturasa/metabolismoRESUMEN
Starting from a known piperazine-based SCD-1 inhibitor, we obtained more potent benzoylpiperidine analogs. Optimization of the structure of the benzoylpiperidine-based SCD-1 inhibitors resulted in the identification of 6-[4-(2-methylbenzoyl)piperidin-1-yl]pyridazine-3-carboxylic acid (2-hydroxy-2-pyridin-3-yl-ethyl)amide (24) which showed strong inhibitory activity against both human and murine SCD-1. In addition, this compound exhibited good oral bioavailability and demonstrated plasma triglyceride lowering effects in Zucker fatty rats in a dose-dependent manner after a 7-day oral administration (qd).
Asunto(s)
Inhibidores Enzimáticos/química , Hipoglucemiantes/química , Piperidinas/química , Piridazinas/química , Piridinas/química , Estearoil-CoA Desaturasa/antagonistas & inhibidores , Triglicéridos/sangre , Administración Oral , Animales , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/farmacocinética , Humanos , Hipoglucemiantes/síntesis química , Hipoglucemiantes/farmacocinética , Ratones , Microsomas Hepáticos/metabolismo , Piperidinas/síntesis química , Piperidinas/farmacocinética , Piridazinas/síntesis química , Piridazinas/farmacología , Piridinas/síntesis química , Piridinas/farmacología , Ratas , Ratas Zucker , Estearoil-CoA Desaturasa/metabolismoRESUMEN
To establish allylic substitution of secondary allylic alcohol derivatives with alkynyl copper reagents, allylic esters bearing the (2-pyridine)CO2-, (2-pyrazine)CO2-, (EtO)2PO2-, C6F5CO2-, o-(Ph2P)C6H4CO2-, MeOCO2-, or AcO- group were examined. First, picolinate (R1 = Me, R2 = CH2OPMB) was subjected to reaction with (TMS-C[triple bond]C)2CuLi.LiBr at 0degreesC. Although no substitution took place, MgBr2 (3 equiv) was found to promote the reaction to produce the anti SN2' product in 93% yield with 94% regioselectivity and 99% chirality transfer. In contrast, substitution of the other esters with the copper reagent in the presence of MgBr2 were less reactive ((2-pyrazine)CO2-) or marginally reactive (other cases). Generality of the substitution using picolinates was established with five picolinates (R1 = Me, Ph(CH2)2, PMBO(CH2)3; R2 = Me, CH2OPMB, CH2OTBS, C5H11, c-C6H11) and seven alkynyl copper reagents (R3 = TMS, Ph, p-TBSOC6H4, p- and o-MeOC6H4, p-MeC6H4, p-FC6H4), furnishing anti SN2' products in 61-93% yields with high regioselectivity (usually >90%) and high chirality transfer (usually >95%). In addition, transformation of the products was briefly studied.
Asunto(s)
Alquinos/química , Alquinos/síntesis química , Compuestos Alílicos/química , Cobre/química , Compuestos Organometálicos/química , Ácidos Picolínicos/química , Estructura Molecular , EstereoisomerismoRESUMEN
A series of structurally novel stearoyl-CoA desaturase-1 (SCD-1) inhibitors has been identified by optimizing a hit from our corporate library. Preliminary structure-activity relationship (SAR) studies led to the discovery of the highly potent and orally bioavailable thiazole-based SCD-1 inhibitor, 3-(2-hydroxyethoxy)-4-methoxy-N-[5-(3-trifluoromethylbenzyl)thiazol-2-yl]benzamide (23a).
Asunto(s)
Benzamidas/síntesis química , Química Farmacéutica/métodos , Inhibidores Enzimáticos/síntesis química , Estearoil-CoA Desaturasa/antagonistas & inhibidores , Tiazoles/síntesis química , Administración Oral , Animales , Área Bajo la Curva , Benzamidas/farmacología , Diseño de Fármacos , Inhibidores Enzimáticos/farmacología , Humanos , Concentración 50 Inhibidora , Ratones , Ratones Endogámicos C57BL , Modelos Químicos , Estearoil-CoA Desaturasa/química , Relación Estructura-Actividad , Tiazoles/química , Tiazoles/farmacologíaRESUMEN
The continuing investigation of SAR studies of 3-(2-hydroxyethoxy)-N-(5-benzylthiazol-2-yl)-benzamides as stearoyl-CoA desaturase-1 (SCD-1) inhibitors is reported. Our prior hit-to-lead effort resulted in the identification of 1a as a potent and orally efficacious SCD-1 inhibitor. Further optimization of the structural motif resulted in the identification of 4-ethylamino-3-(2-hydroxyethoxy)-N-[5-(3-trifluoromethylbenzyl)thiazol-2-yl]benzamide (37c) with sub nano molar IC(50) in both murine and human SCD-1 inhibitory assays. This compound demonstrated a dose-dependent decrease in the plasma desaturation index in C57BL/6J mice on a non-fat diet after 7 days of oral administration.
Asunto(s)
Benzamidas/síntesis química , Química Farmacéutica/métodos , Estearoil-CoA Desaturasa/antagonistas & inhibidores , Tiazoles/síntesis química , Administración Oral , Animales , Área Bajo la Curva , Benzamidas/farmacología , Relación Dosis-Respuesta a Droga , Diseño de Fármacos , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/farmacología , Humanos , Concentración 50 Inhibidora , Ratones , Ratones Endogámicos C57BL , Modelos Químicos , Estearoil-CoA Desaturasa/química , Relación Estructura-Actividad , Tiazoles/química , Tiazoles/farmacologíaRESUMEN
High regioselectivity for allylic substitution of the cyclopentenyl picolinate 5 with benzylcopper reagent was attained with ZnBr(2), and the finding was applied to the p-BrC(6)H(4)CH(2) reagent. The cyclopentene moiety in the product was reduced to the cyclopentane, and the p-BrC(6)H(4) was converted to the "Cu"C(6)H(4) for the second allylic substitution with picolinate 8 to furnish the title compound after oxidative cleavage of the resulting olefin moiety.
Asunto(s)
Compuestos Alílicos/química , Ciclopentanos/síntesis química , Fenilpropionatos/síntesis química , Catálisis , Ciclopentanos/química , Estructura Molecular , Oxidación-Reducción , Fenilpropionatos/química , Fenilpropionatos/farmacología , Ácidos Picolínicos/químicaRESUMEN
Allylic substitution with sp(2)-carbon reagents (aryl and alkenyl anions) was realized by using allylic picolinates and copper reagents derived from RMgBr and CuBr x Me(2)S to afford anti S(N)2' products regio- and stereoselectively. Steric and electronic factors in the reagents and the size of the methylene substituents around the allylic moiety marginally affected the selectivity. The reaction system was compatible with alkyl reagents as well. Furthermore, the substitution was applied to construction of a quaternary center and synthesis of (-)-sesquichamaenol. Electron-withdrawing nature of the pyridyl group and chelation of the C(=O)-C(5)H(4)N to MgBr(2) generated in situ were found to be responsible for the high efficiency of the substitution.
Asunto(s)
Alquenos/síntesis química , Compuestos Alílicos/química , Cobre/química , Compuestos Organometálicos/química , Alquenos/química , Estructura Molecular , EstereoisomerismoRESUMEN
The picolinoxy group was found to be an extremely powerful leaving group for allylic substitution with aryl nucleophiles derived from ArMgBr and CuBr*Me2S. The substitution proceeds with anti SN2' pathway and with high chirality transfer. The electron-withdrawing effect of the pyridyl group and chelation to MgBr2 are likely the origin of success. Results suggesting these effects were obtained.
Asunto(s)
Compuestos Alílicos/síntesis química , Ácidos Picolínicos/química , Piperidinas/química , Compuestos Alílicos/química , Aniones , Indicadores y Reactivos/síntesis química , Indicadores y Reactivos/química , Estructura Molecular , EstereoisomerismoRESUMEN
Anti-SN2' mode of allylation of the monoester of 4-cyclopentene-1,3-diol with aryl and alkenyl anions was achieved, for the first time, with the MeOCH2CO2- group as a leaving group to which R-ZnBr and CuCl (as a catalyst) were best fitted. The aryl groups successfully installed were Ph, o- and p-MeC6H4, o-MOMOC6H4, o-MeOC6H4, and p-F-C6H4, while cis and trans alkenyl groups were attached with retention of the olefinic stereochemistries.