RESUMEN
Herein we report the design and synthesis of a series of novel bicyclic DGAT1 inhibitors with a carboxylic acid moiety. The optimization of the initial lead compound 7 based on in vitro and in vivo activity led to the discovery of potent indoline and quinoline classes of DGAT1 inhibitors. The structure-activity relationship studies of these novel series of bicyclic carboxylic acid derivatives as DGAT1 inhibitors are described.
Asunto(s)
Ácidos Carboxílicos/farmacología , Diacilglicerol O-Acetiltransferasa/antagonistas & inhibidores , Descubrimiento de Drogas , Inhibidores Enzimáticos/farmacología , Quinolonas/farmacología , Animales , Ácidos Carboxílicos/síntesis química , Ácidos Carboxílicos/química , Diacilglicerol O-Acetiltransferasa/metabolismo , Relación Dosis-Respuesta a Droga , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/química , Humanos , Ratones , Modelos Moleculares , Estructura Molecular , Quinolonas/síntesis química , Quinolonas/química , Relación Estructura-ActividadRESUMEN
A novel series of non-imidazole bicyclic and tricyclic histamine H3 receptor antagonists has been discovered. Compound 17 was identified as a centrally penetrant molecule with high receptor occupancy which demonstrates robust oral activity in rodent models of obesity. In addition compound 17 possesses clean CYP and hERG profiles and shows no behavioral changes in the Irwin test.
Asunto(s)
Antagonistas de los Receptores Histamínicos H3/química , Antagonistas de los Receptores Histamínicos H3/uso terapéutico , Obesidad/tratamiento farmacológico , Animales , Antagonistas de los Receptores Histamínicos H3/metabolismo , Antagonistas de los Receptores Histamínicos H3/farmacocinética , Humanos , Microsomas Hepáticos/metabolismo , Ratas , Receptores Histamínicos H3/metabolismoRESUMEN
A scaffold hopping strategy was successfully applied in discovering 2-aminooxazole amides as potent DGAT1 inhibitors for the treatment of dyslipidemia. Further optimization in potency and PK properties resulted in a lead series with oral in vivo efficacy in a mouse postprandial triglyceridemia (PPTG) assay.
Asunto(s)
Amidas/farmacología , Diacilglicerol O-Acetiltransferasa/antagonistas & inhibidores , Inhibidores Enzimáticos/farmacología , Oxazoles/farmacología , Triglicéridos/sangre , Animales , Humanos , Ratones , Estructura Molecular , Relación Estructura-ActividadRESUMEN
Inhibitors based on a benzo-fused spirocyclic oxazepine scaffold were discovered for stearoyl-coenzyme A (CoA) desaturase 1 (SCD1) and subsequently optimized to potent compounds with favorable pharmacokinetic profiles and in vivo efficacy in reducing the desaturation index in a mouse model. Initial optimization revealed potency preferences for the oxazepine core and benzylic positions, while substituents on the piperidine portions were more tolerant and allowed for tuning of potency and PK properties. After preparation and testing of a range of functional groups on the piperidine nitrogen, three classes of analogs were identified with single digit nanomolar potency: glycine amides, heterocycle-linked amides, and thiazoles. Responding to concerns about target localization and potential mechanism-based side effects, an initial effort was also made to improve liver concentration in an available rat PK model. An advanced compound 17m with a 5-carboxy-2-thiazole substructure appended to the spirocyclic piperidine scaffold was developed which satisfied the in vitro and in vivo requirements for more detailed studies.
Asunto(s)
Dibenzoxazepinas/síntesis química , Sistemas de Liberación de Medicamentos , Inhibidores Enzimáticos/síntesis química , Hígado/enzimología , Estearoil-CoA Desaturasa/antagonistas & inhibidores , Animales , Ciclización , Dibenzoxazepinas/farmacocinética , Dibenzoxazepinas/farmacología , Activación Enzimática/efectos de los fármacos , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/farmacología , Ratones , Modelos Animales , Estructura Molecular , Ratas , Compuestos de Espiro/síntesis química , Compuestos de Espiro/farmacocinética , Compuestos de Espiro/farmacologíaRESUMEN
The structure-activity relationship studies of a novel series of carboxylic acid derivatives of pyridine-carboxamides as DGAT-1 inhibitors is described. The optimization of the initial lead compound 6 based on in vitro and in vivo activity led to the discovery of key compounds 10j and 17h.
Asunto(s)
Amidas/farmacología , Diacilglicerol O-Acetiltransferasa/antagonistas & inhibidores , Inhibidores Enzimáticos/farmacología , Piridinas/farmacología , Animales , Diacilglicerol O-Acetiltransferasa/metabolismo , Inhibidores Enzimáticos/química , Humanos , Ratones , Relación Estructura-ActividadRESUMEN
The synthesis and SAR of a novel series of 4-azabenzoxazole histamine H(3) antagonists is described. Introduction of substituted phenyl, pyridyl and fused heterocyclic groups to the 6-position of the 4-azabenzoxazole core gave a series of compounds with good H(3) antagonist activity in both ex vivo and in vivo assays.
Asunto(s)
Benzoxazoles/química , Benzoxazoles/farmacología , Antagonistas de los Receptores Histamínicos H3/química , Antagonistas de los Receptores Histamínicos H3/farmacología , Receptores Histamínicos H3/metabolismo , Animales , Compuestos Aza/síntesis química , Compuestos Aza/química , Compuestos Aza/farmacocinética , Compuestos Aza/farmacología , Benzoxazoles/síntesis química , Benzoxazoles/farmacocinética , Antagonistas de los Receptores Histamínicos H3/síntesis química , Antagonistas de los Receptores Histamínicos H3/farmacocinética , Humanos , Ratones , Ratas , Relación Estructura-ActividadRESUMEN
A structure-activity relationship study was undertaken to address the lack of oral exposure of the H3 antagonist 1, which incorporated an arylketone. Among a number of sub-series, the 4H-pyrido[1,2-a]pyrimidin-4-one analog 21 showed an improved PK profile in rat and mouse and was active in an obesity model. The pyrimidin-4-one proved to be a novel and useful ketone bioisostere.
Asunto(s)
Antagonistas de los Receptores Histamínicos H3/farmacocinética , Tiadiazoles/farmacología , Administración Oral , Animales , Cetonas , Obesidad/tratamiento farmacológico , Ratas , Relación Estructura-Actividad , Tiadiazoles/farmacocinéticaRESUMEN
Antagonism of the adenosine A(2A) receptor affords a possible treatment of Parkinson's disease. In the course of investigating pyrazolo[4,3-e]-1,2,4-triazolo[1,5-c]pyrimidine A(2A) antagonists, we prepared [1,2,4]-triazolo[4,3-c]pyrimidin-3-ones with potent and selective (vs A(1)) A(2A) antagonist activity. Structure-activity relationships are described for this series.
Asunto(s)
Antagonistas del Receptor de Adenosina A2/química , Receptor de Adenosina A2A/química , Antagonistas del Receptor de Adenosina A2/síntesis química , Antagonistas del Receptor de Adenosina A2/uso terapéutico , Humanos , Enfermedad de Parkinson/tratamiento farmacológico , Pirimidinonas/síntesis química , Pirimidinonas/química , Pirimidinonas/uso terapéutico , Receptor de Adenosina A2A/metabolismo , Relación Estructura-ActividadRESUMEN
A series of 2-piperidinopiperidine-5-arylthiadiazoles was synthesized and subjected to a structure-activity relationship (SAR) investigation. The potency of this series was improved to the single digit nanomolar range. The key analogs were shown to be free of P450 issues, and they also maintained good ex vivo activity and brain penetration.
Asunto(s)
Antagonistas de los Receptores Histamínicos/química , Antagonistas de los Receptores Histamínicos/farmacología , Receptores Histamínicos H3/metabolismo , Tiadiazoles/química , Tiadiazoles/farmacología , Animales , Encéfalo/metabolismo , Antagonistas de los Receptores Histamínicos/farmacocinética , Humanos , Ratones , Ratas , Relación Estructura-Actividad , Tiadiazoles/farmacocinéticaRESUMEN
A series of novel benzazepine derived dopamine D(1) antagonists have been discovered. These compounds are highly potent at D(1) and showed excellent selectivity over D(2) and D(4) receptors. SAR studies revealed that a variety of functional groups are tolerated on the D-ring of known tetracyclic benzazepine analog 2, SCH 39166, leading to compounds with nanomolar potency at D(1) and good selectivity over D(2)-like receptors.
Asunto(s)
Benzazepinas/química , Antagonistas de Dopamina/química , Receptores de Dopamina D1/antagonistas & inhibidores , Animales , Benzazepinas/farmacología , Antagonistas de Dopamina/farmacología , Masculino , Unión Proteica/efectos de los fármacos , Unión Proteica/fisiología , Ratas , Ratas Sprague-Dawley , Receptores de Dopamina D1/fisiologíaRESUMEN
Modification of prototype NK(1) antagonist 2 resulted in the synthesis of a series of simple amides 6 and retroamides 9. These compounds were shown to be potent and orally active NK(1) antagonists.
Asunto(s)
Antagonistas del Receptor de Neuroquinina-1 , Piperidinas/síntesis química , Piperidinas/farmacología , Animales , Área Bajo la Curva , Cromatografía Líquida de Alta Presión , Gerbillinae , Semivida , Piperidinas/farmacocinética , Ratas , Estereoisomerismo , Relación Estructura-ActividadRESUMEN
A series of novel dopamine D(1) antagonists derived from functionalization of the D-ring of SCH 39166 were prepared. A number of these compounds displayed subnanomolar D(1) activity and more than 1000-fold selectivity over D(2). We found C-3 derivatization afforded compounds with superior overall profile in comparison to the C-2 and C-4 derivatization. A number of highly potent D(1) antagonists were discovered which have excellent selectivity over other dopamine receptors and improved PK profile compared to SCH 39166.
Asunto(s)
Benzazepinas/química , Benzazepinas/farmacología , Antagonistas de Dopamina/química , Antagonistas de Dopamina/farmacología , Receptores de Dopamina D1/antagonistas & inhibidores , Animales , Ratas , Receptores de Dopamina D1/fisiologíaRESUMEN
The syntheses and SAR investigations of novel CB(1) receptor antagonists based on a 1,2-diaryl piperidine core have been described. Optimization of this core afforded a compound with robust in vivo potency by reducing food intake in a mouse DIO model.
Asunto(s)
Piperidinas/química , Piperidinas/farmacología , Receptor Cannabinoide CB1/antagonistas & inhibidores , Animales , Dieta/efectos adversos , Ingestión de Alimentos/efectos de los fármacos , Ingestión de Alimentos/fisiología , Ratones , Ratones Obesos , Obesidad/etiología , Obesidad/metabolismo , Piperidinas/administración & dosificación , Unión Proteica/fisiología , Receptor Cannabinoide CB1/metabolismo , Relación Estructura-ActividadRESUMEN
The Wnt/ß-catenin signaling pathway has been implicated in human proliferative diseases such as cancer and fibrosis. The functions of ß-catenin and several other components of this pathway have been investigated in fibrosis. However, the potential role of R-spondin proteins (RSPOs), enhancers of the Wnt/ß-catenin signaling, has not been described. A specific interventional strategy targeting this pathway for fibrosis remains to be defined. We developed monoclonal antibodies against members of the RSPO family (RSPO1, 2, and 3) and probed their potential function in fibrosis in vivo. We demonstrated that RSPO3 plays a critical role in the development of fibrosis in multiple organs. Specifically, an anti-RSPO3 antibody, OMP-131R10, when dosed therapeutically, attenuated fibrosis in carbon tetrachloride (CCl4)-induced liver fibrosis, bleomycin-induced pulmonary and skin fibrosis models. Mechanistically, we showed that RSPO3 induces multiple pro-fibrotic chemokines and cytokines in Kupffer cells and hepatocytes. We found that the anti-fibrotic activity of OMP-131R10 is associated with its inhibition of ß-catenin activation in vivo. Finally, RSPO3 was found to be highly elevated in the active lesions of fibrotic tissues in mouse models of fibrosis and in patients with idiopathic pulmonary fibrosis (IPF) and nonalcoholic steatohepatitis (NASH). Together these data provide an anti-fibrotic strategy for targeting the Wnt/ß-catenin pathway through RSPO3 blockade and support that OMP-131R10 could be an important therapeutic agent for fibrosis.
Asunto(s)
Anticuerpos/uso terapéutico , Fibrosis Pulmonar Idiopática , Enfermedad del Hígado Graso no Alcohólico , Trombospondinas/fisiología , Animales , Células Cultivadas , Humanos , Fibrosis Pulmonar Idiopática/tratamiento farmacológico , Fibrosis Pulmonar Idiopática/metabolismo , Masculino , Ratones , Ratones Endogámicos DBA , Enfermedad del Hígado Graso no Alcohólico/tratamiento farmacológico , Enfermedad del Hígado Graso no Alcohólico/metabolismo , Vía de Señalización Wnt/efectos de los fármacosRESUMEN
The adenosine A(2A) receptor has been implicated in the underlying biology of various neurological and psychiatric disorders, including Parkinson's disease (PD) and depression. Preladenant and SCH 412348 [7-[2-[4-2,4-difluorophenyl]-1-piperazinyl]ethyl]-2-(2-furanyl)-7H-pyrazolo[4,3-e][1,2,4]triazolo[1,5-c]pyrimidin-5-amine] are potent competitive antagonists of the human A(2A) receptor (K(i) = 1.1 and 0.6 nM, respectively) and have >1000-fold selectivity over all other adenosine receptors, making these compounds the most selective A(2A) receptor antagonists reported to date. Both compounds attenuate hypolocomotion induced by the A(2A) receptor agonist CGS-21680 [2-[p-(2-carboxyethyl)phenethylamino]-5'-N-ethylcarboxamidoadenosine], suggesting that they inhibit A(2A) receptor activity in vivo. Their high degree of selectivity and robust in vivo activity make preladenant and SCH 412348 useful tools to investigate the role of the A(2A) receptor system in animal models of PD and depression. Oral administration of preladenant and SCH 412348 (0.1-1 mg/kg) to rats potentiated 3,4-dihydroxy-L-phenylalanine (L-Dopa)-induced contralateral rotations after 6-hydroxydopamine lesions in the medial forebrain bundle and potently attenuated the cataleptic effects of haloperidol. Preladenant (1 mg/kg) inhibited L-Dopa-induced behavioral sensitization after repeated daily administration, which suggests a reduced risk of the development of dyskinesias. Finally, preladenant and SCH 412348 exhibited antidepressant-like profiles in models of behavioral despair, namely the mouse tail suspension test and the mouse and rat forced swim test. These studies demonstrate that preladenant and SCH 412348 are potent and selective A(2A) receptor antagonists and provide further evidence of the potential therapeutic benefits of A(2A) receptor inhibition in PD (with reduced risk of dyskinesias) and depression (one of the primary nonmotor symptoms of PD).
Asunto(s)
Antagonistas del Receptor de Adenosina A2 , Trastorno Depresivo/tratamiento farmacológico , Modelos Animales de Enfermedad , Trastornos del Movimiento/tratamiento farmacológico , Fármacos Neuroprotectores/farmacología , Pirimidinas/farmacología , Triazoles/farmacología , Animales , Células CHO , Cricetinae , Cricetulus , Trastorno Depresivo/metabolismo , Humanos , Masculino , Ratones , Trastornos del Movimiento/metabolismo , Fármacos Neuroprotectores/química , Pirimidinas/química , Ratas , Receptor de Adenosina A2A/metabolismo , Triazoles/químicaRESUMEN
A series of novel 1,3-benzodiazapine based D1 antagonists was designed according to the understanding of pharmacophore models derived from SCH 23390 (1b), a potent and selective D1 antagonist. The new design features an achiral cyclic-amidine that maintains desired basicity. Solid phase synthesis was developed for SAR development of the novel dopamine antagonists.
Asunto(s)
Benzodiazepinas/química , Antagonistas de Dopamina/química , Neurotransmisores/química , Receptores de Dopamina D1/antagonistas & inhibidores , Benzazepinas/química , Benzazepinas/farmacología , Benzodiazepinas/síntesis química , Benzodiazepinas/farmacología , Antagonistas de Dopamina/síntesis química , Antagonistas de Dopamina/farmacología , Antagonistas de los Receptores de Dopamina D2 , Diseño de Fármacos , Humanos , Neurotransmisores/síntesis química , Neurotransmisores/farmacología , Receptores de Dopamina D1/metabolismo , Receptores de Dopamina D2/metabolismo , Relación Estructura-ActividadRESUMEN
A series of 2-(1,4'-bipiperidine-1'-yl)thiazolopyridines was synthesized and evaluated as a new lead of non-imidazole histamine H(3) receptor antagonists. Introduction of diversity at the 6-position of the pyridine ring was designed to enhance in vitro potency and decrease hERG activity. The structure-activity relationships for these new thiazolopyridine antagonists are discussed.
Asunto(s)
Antagonistas de los Receptores Histamínicos/química , Piridinas/química , Receptores Histamínicos H3/química , Animales , Haplorrinos , Antagonistas de los Receptores Histamínicos/síntesis química , Antagonistas de los Receptores Histamínicos/farmacocinética , Humanos , Ratones , Ratones Endogámicos ICR , Microsomas Hepáticos/metabolismo , Piridinas/síntesis química , Piridinas/farmacocinética , Ratas , Receptores Histamínicos H3/metabolismo , Proteínas Recombinantes/química , Proteínas Recombinantes/metabolismo , Relación Estructura-Actividad , Transactivadores/metabolismo , Regulador Transcripcional ERGRESUMEN
Antagonism of the adenosine A(2a) receptor offers great promise in the treatment of Parkinson's disease. In the course of exploring pyrazolo[4,3-e]-1,2,4-triazolo[1,5-c]pyrimidine A(2A) antagonists, which led to clinical candidate SCH 420814, we prepared 1,2,4-triazolo[1,5-c]pyrimidines with potent and selective (vs A(1)) A(2a) antagonist activity, including oral activity in the rat haloperidol-induced catalepsy model. Structure-activity relationships and plasma levels are described for this series.
Asunto(s)
Antagonistas del Receptor de Adenosina A2 , Enfermedad de Parkinson/tratamiento farmacológico , Pirimidinas/farmacología , Triazoles/síntesis química , Administración Oral , Animales , Área Bajo la Curva , Catalepsia , Química Farmacéutica/métodos , Diseño de Fármacos , Haloperidol/farmacología , Modelos Químicos , Pirimidinas/síntesis química , Pirimidinas/química , Ratas , Relación Estructura-Actividad , Triazoles/farmacologíaRESUMEN
SCH 58261 is a reported adenosine A(2A) receptor antagonist, which is active in rat in vivo models of Parkinson's Disease upon ip administration. However, it has poor selectivity versus the A(1) receptor and does not demonstrate oral activity. We report the design and synthesis of biaryl and heteroaryl analogs of SCH 58261 which improve the A(2A) receptor binding selectivity as well as the pharmacokinetic properties of SCH 58261. In particular, the quinoline 25 has excellent A(2A) receptor in vitro binding affinity and selectivity, sustained rat plasma levels upon oral dosing, and is active orally in a rat behavioral assay.
Asunto(s)
Antagonistas del Receptor de Adenosina A2 , Química Farmacéutica/métodos , Fármacos Neuroprotectores/síntesis química , Fármacos Neuroprotectores/farmacología , Enfermedad de Parkinson/tratamiento farmacológico , Pirimidinas/síntesis química , Pirimidinas/farmacología , Triazoles/síntesis química , Triazoles/farmacología , Administración Oral , Animales , Conducta Animal/efectos de los fármacos , Diseño de Fármacos , Humanos , Modelos Químicos , Piperazinas/química , Quinolinas/química , Ratas , Relación Estructura-ActividadRESUMEN
SCH 58261 is a reported adenosine A(2A) receptor antagonist which is active in rat in vivo models of Parkinson's Disease upon ip administration. However, it has poor selectivity versus the A(1) receptor and does not demonstrate oral activity. Quinoline analogs have improved upon the selectivity and pharmacokinetics of SCH 58261, but were difficult to handle due to poor aqueous solubility. We report the design and synthesis of fused heterocyclic analogs of SCH 58261 with aqueous solubility as well as improved A(2A) receptor binding selectivity and pharmacokinetic properties. In particular, the tetrahydronaphthyridine 4s has excellent A(2A) receptor in vitro binding affinity and selectivity, is active orally in a rat in vivo model of Parkinson's Disease, and has aqueous solubility of 100 microM at physiological pH.