RESUMEN
The selective inhibition of RET kinase as a treatment for relevant cancer types including lung adenocarcinoma has garnered considerable interest in recent years and prompted a variety of efforts toward the discovery of small-molecule therapeutics. Hits uncovered via the analysis of archival kinase data ultimately led to the identification of a promising pyrrolo[2,3-d]pyrimidine scaffold. The optimization of this pyrrolo[2,3-d]pyrimidine core resulted in compound 1, which demonstrated potent in vitro RET kinase inhibition and robust in vivo efficacy in RET-driven tumor xenografts upon multiday dosing in mice. The administration of 1 was well-tolerated at established efficacious doses (10 and 30 mg/kg, po, qd), and plasma exposure levels indicated a minimal risk of KDR or hERG inhibition in vivo, as evaluated by Miles assay and free plasma concentrations, respectively.
RESUMEN
RET (REarranged during Transfection) kinase gain-of-function aberrancies have been identified as potential oncogenic drivers in lung adenocarcinoma, along with several other cancer types, prompting the discovery and assessment of selective inhibitors. Internal mining and analysis of relevant kinase data informed the decision to investigate a pyrazolo[1,5-a]pyrimidine scaffold, where subsequent optimization led to the identification of compound WF-47-JS03 (1), a potent RET kinase inhibitor with >500-fold selectivity against KDR (Kinase insert Domain Receptor) in cellular assays. In subsequent mouse in vivo studies, compound 1 demonstrated effective brain penetration and was found to induce strong regression of RET-driven tumor xenografts at a well-tolerated dose (10 mg/kg, po, qd). Higher doses of 1, however, were poorly tolerated in mice, similar to other pyrazolo[1,5-a]pyrimidine compounds at or near the efficacious dose, and indicative of the narrow therapeutic windows seen with this scaffold.
RESUMEN
Direct pharmacological inhibition of RAS has remained elusive, and efforts to target CRAF have been challenging due to the complex nature of RAF signaling, downstream of activated RAS, and the poor overall kinase selectivity of putative RAF inhibitors. Herein, we describe 15 (LXH254, Aversa, R.; et al. Int. Patent WO2014151616A1, 2014), a selective B/C RAF inhibitor, which was developed by focusing on drug-like properties and selectivity. Our previous tool compound, 3 (RAF709; Nishiguchi, G. A.; et al. J. Med. Chem. 2017, 60, 4969), was potent, selective, efficacious, and well tolerated in preclinical models, but the high human intrinsic clearance precluded further development and prompted further investigation of close analogues. A structure-based approach led to a pyridine series with an alcohol side chain that could interact with the DFG loop and significantly improved cell potency. Further mitigation of human intrinsic clearance and time-dependent inhibition led to the discovery of 15. Due to its excellent properties, it was progressed through toxicology studies and is being tested in phase 1 clinical trials.
Asunto(s)
Antineoplásicos/química , Descubrimiento de Drogas/métodos , Mutación/genética , Inhibidores de Proteínas Quinasas/química , Proteínas Proto-Oncogénicas B-raf/antagonistas & inhibidores , Proteínas Proto-Oncogénicas B-raf/genética , Animales , Antineoplásicos/farmacología , Diseño de Fármacos , Descubrimiento de Drogas/tendencias , Humanos , Simulación del Acoplamiento Molecular/métodos , Simulación del Acoplamiento Molecular/tendencias , Mutación/efectos de los fármacos , Inhibidores de Proteínas Quinasas/farmacología , Ensayos Antitumor por Modelo de Xenoinjerto/métodosRESUMEN
Resistance to the RAF inhibitor vemurafenib arises commonly in melanomas driven by the activated BRAF oncogene. Here, we report antitumor properties of RAF709, a novel ATP-competitive kinase inhibitor with high potency and selectivity against RAF kinases. RAF709 exhibited a mode of RAF inhibition distinct from RAF monomer inhibitors such as vemurafenib, showing equal activity against both RAF monomers and dimers. As a result, RAF709 inhibited MAPK signaling activity in tumor models harboring either BRAFV600 alterations or mutant N- and KRAS-driven signaling, with minimal paradoxical activation of wild-type RAF. In cell lines and murine xenograft models, RAF709 demonstrated selective antitumor activity in tumor cells harboring BRAF or RAS mutations compared with cells with wild-type BRAF and RAS genes. RAF709 demonstrated a direct pharmacokinetic/pharmacodynamic relationship in in vivo tumor models harboring KRAS mutation. Furthermore, RAF709 elicited regression of primary human tumor-derived xenograft models with BRAF, NRAS, or KRAS mutations with excellent tolerability. Our results support further development of inhibitors like RAF709, which represents a next-generation RAF inhibitor with unique biochemical and cellular properties that enables antitumor activities in RAS-mutant tumors.Significance: In an effort to develop RAF inhibitors with the appropriate pharmacological properties to treat RAS mutant tumors, RAF709, a compound with potency, selectivity, and in vivo properties, was developed that will allow preclinical therapeutic hypothesis testing, but also provide an excellent probe to further unravel the complexities of RAF kinase signaling. Cancer Res; 78(6); 1537-48. ©2018 AACR.
Asunto(s)
2,2'-Dipiridil/análogos & derivados , Antineoplásicos/farmacología , Benzamidas/farmacología , Proteínas Proto-Oncogénicas B-raf/genética , Quinasas raf/antagonistas & inhibidores , Proteínas ras/genética , 2,2'-Dipiridil/farmacología , Animales , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Resistencia a Antineoplásicos/efectos de los fármacos , Femenino , Humanos , Quinasas Quinasa Quinasa PAM/antagonistas & inhibidores , Ratones Desnudos , Mutación , Inhibidores de Proteínas Quinasas/farmacología , Multimerización de Proteína , Ensayos Antitumor por Modelo de Xenoinjerto , Quinasas raf/metabolismoRESUMEN
RAS oncogenes have been implicated in >30% of human cancers, all representing high unmet medical need. The exquisite dependency on CRAF kinase in KRAS mutant tumors has been established in genetically engineered mouse models and human tumor cells. To date, many small molecule approaches are under investigation to target CRAF, yet kinase-selective and cellular potent inhibitors remain challenging to identify. Herein, we describe 14 (RAF709) [ Aversa , Biaryl amide compounds as kinase inhibitors and their preparation . WO 2014151616, 2014 ], a selective B/C RAF inhibitor, which was developed through a hypothesis-driven approach focusing on drug-like properties. A key challenge encountered in the medicinal chemistry campaign was maintaining a balance between good solubility and potent cellular activity (suppression of pMEK and proliferation) in KRAS mutant tumor cell lines. We investigated the small molecule crystal structure of lead molecule 7 and hypothesized that disruption of the crystal packing would improve solubility, which led to a change from N-methylpyridone to a tetrahydropyranyl oxy-pyridine derivative. 14 proved to be soluble, kinase selective, and efficacious in a KRAS mutant xenograft model.
Asunto(s)
2,2'-Dipiridil/análogos & derivados , Antineoplásicos/farmacología , Benzamidas/farmacología , Quinasas raf/antagonistas & inhibidores , Proteínas ras/genética , 2,2'-Dipiridil/química , 2,2'-Dipiridil/farmacología , Animales , Antineoplásicos/química , Antineoplásicos/farmacocinética , Benzamidas/química , Cristalografía por Rayos X , Perros , Diseño de Fármacos , Descubrimiento de Drogas , Estabilidad de Medicamentos , Humanos , Concentración 50 Inhibidora , Ratones , Terapia Molecular Dirigida , Neoplasias/tratamiento farmacológico , Neoplasias/genética , Proteínas Proto-Oncogénicas B-raf/química , Proteínas Proto-Oncogénicas p21(ras)/genética , Ratas , Relación Estructura-Actividad , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
ATP competitive inhibitors of the BRAF(V600E) oncogene paradoxically activate downstream signaling in cells bearing wild-type BRAF (BRAF(WT)). In this study, we investigate the biochemical mechanism of wild-type RAF (RAF(WT)) activation by multiple catalytic inhibitors using kinetic analysis of purified BRAF(V600E) and RAF(WT) enzymes. We show that activation of RAF(WT) is ATP dependent and directly linked to RAF kinase activity. These data support a mechanism involving inhibitory autophosphorylation of RAF's phosphate-binding loop that, when disrupted either through pharmacologic or genetic alterations, results in activation of RAF and the mitogen-activated protein kinase (MAPK) pathway. This mechanism accounts not only for compound-mediated activation of the MAPK pathway in BRAF(WT) cells but also offers a biochemical mechanism for BRAF oncogenesis.
Asunto(s)
Sistema de Señalización de MAP Quinasas/efectos de los fármacos , Quinasas raf/antagonistas & inhibidores , Adenosina Trifosfato/metabolismo , Adenosina Trifosfato/fisiología , Línea Celular Tumoral , Humanos , Fosforilación/efectos de los fármacos , Proteínas Proto-Oncogénicas B-raf/genética , Proteínas Proto-Oncogénicas B-raf/metabolismo , Proteínas Proto-Oncogénicas B-raf/fisiología , Proteínas Proto-Oncogénicas c-raf/genética , Proteínas Proto-Oncogénicas c-raf/metabolismo , Proteínas Proto-Oncogénicas c-raf/fisiología , Quinasas raf/genética , Quinasas raf/metabolismoRESUMEN
The biological functions of the aryl hydrocarbon receptor (AHR) can be delineated into dioxin response element (DRE)-dependent or -independent activities. Ligands exhibiting either full or partial agonist activity, e.g., 2,3,7,8-tetrachlorodibenzo-p-dioxin and α-naphthoflavone, have been demonstrated to potentiate both DRE-dependent and -independent AHR function. In contrast, the recently identified selective AHR modulators (SAhRMs), e.g., 1-allyl-3-(3,4-dimethoxyphenyl)-7-(trifluoromethyl)-1H-indazole (SGA360), bias AHR toward DRE-independent functionality while displaying antagonism with regard to ligand-induced DRE-dependent transcription. Recent studies have expanded the physiological role of AHR to include modulation of hematopoietic progenitor expansion and immunoregulation. It remains to be established whether such physiological roles are mediated through DRE-dependent or -independent pathways. Here, we present evidence for a third class of AHR ligand, "pure" or complete antagonists with the capacity to suppress both DRE-dependent and -independent AHR functions, which may facilitate dissection of physiological AHR function with regard to DRE or non-DRE-mediated signaling. Competitive ligand binding assays together with in silico modeling identify N-(2-(1H-indol-3-yl)ethyl)-9-isopropyl-2-(5-methylpyridin-3-yl)-9H-purin-6-amine (GNF351) as a high-affinity AHR ligand. DRE-dependent reporter assays, in conjunction with quantitative polymerase chain reaction analysis of AHR targets, reveal GNF351 as a potent AHR antagonist that demonstrates efficacy in the nanomolar range. Furthermore, unlike many currently used AHR antagonists, e.g., α-naphthoflavone, GNF351 is devoid of partial agonist potential. It is noteworthy that in a model of AHR-mediated DRE-independent function, i.e., suppression of cytokine-induced acute-phase gene expression, GNF351 has the capacity to antagonize agonist and SAhRM-mediated suppression of SAA1. Such data indicate that GNF351 is a pure antagonist with the capacity to inhibit both DRE-dependent and -independent activity.
Asunto(s)
Compuestos Alílicos/farmacología , Indazoles/farmacología , Indoles/farmacología , Purinas/farmacología , Receptores de Hidrocarburo de Aril/antagonistas & inhibidores , Receptores de Hidrocarburo de Aril/metabolismo , Compuestos Alílicos/metabolismo , Animales , Sitios de Unión/fisiología , Línea Celular Tumoral , Relación Dosis-Respuesta a Droga , Células Hep G2 , Hepatocitos/efectos de los fármacos , Hepatocitos/metabolismo , Humanos , Indazoles/metabolismo , Indoles/química , Indoles/metabolismo , Ligandos , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Purinas/química , Purinas/metabolismoRESUMEN
Antagonists of the corticotropin-releasing factor (CRF) neuropeptide may prove effective in treating stress and anxiety related disorders. In an effort to identify antagonists with improved physico-chemical properties a new series of CRF(1) antagonists were designed to substitute the propyl groups at the C7 position of the pyrazolo[1,5-a]pyrimidine core of 1 with heterocycles. Compound (S)-8d was identified as a high affinity ligand with a pK(i) value of 8.2 and a functional CRF(1) antagonist with pIC(50) value of 7.0 in the in vitro CRF ACTH production assay.
Asunto(s)
Compuestos de Azabiciclo/química , Oxadiazoles/química , Pirazoles/química , Piridinas/química , Receptores de Hormona Liberadora de Corticotropina/antagonistas & inhibidores , Compuestos de Azabiciclo/síntesis química , Compuestos de Azabiciclo/farmacocinética , Humanos , Microsomas Hepáticos/metabolismo , Oxadiazoles/síntesis química , Oxadiazoles/farmacocinética , Unión Proteica , Receptores de Hormona Liberadora de Corticotropina/genética , Receptores de Hormona Liberadora de Corticotropina/metabolismo , Proteínas Recombinantes/antagonistas & inhibidores , Proteínas Recombinantes/genética , Proteínas Recombinantes/metabolismoRESUMEN
In the present article, we report on a strategy to improve the physical properties of a series of small molecule human adenosine 2A (hA2A) antagonists. One of the aromatic rings typical of this series of antagonists is replaced with a series of aliphatic groups, with the aim of disrupting crystal packing of the molecule to lower the melting point and in turn to improve the solubility. Herein, we describe the SAR of a new series of water-soluble 2,4,6-trisubstituted pyrimidines where R1 is an aromatic heterocycle, R2 is a short-chain alkyl amide, and the typical R3 aromatic heterocyclic substituent is replaced with an aliphatic amino substituent. This approach significantly enhanced aqueous solubility and lowered the log P of the system to provide molecules without significant hERG or CYP liabilities and robust in vivo efficacy.
Asunto(s)
Acetamidas/uso terapéutico , Antagonistas del Receptor de Adenosina A2 , Pirimidinas/uso terapéutico , Acetamidas/síntesis química , Antagonistas del Receptor de Adenosina A1 , Animales , Conducta Animal/efectos de los fármacos , Catalepsia/inducido químicamente , Catalepsia/tratamiento farmacológico , Sinergismo Farmacológico , Haloperidol , Humanos , Pirimidinas/síntesis química , Ratas , Rotación , Solubilidad , Relación Estructura-ActividadRESUMEN
In this report, the strategy and outcome of expanding SAR exploration to improve solubility and metabolic stability are discussed. Compound 35 exhibited excellent potency, selectivity over A(1) and improved solubility of >4 mg/mL at pH 8.0. In addition, compound 35 had good metabolic stability with a scaled intrinsic clearance of 3 mL/min/kg (HLM) and demonstrated efficacy in the haloperidol induced catalepsy model.
Asunto(s)
Antagonistas del Receptor de Adenosina A2 , Aminopiridinas/química , Química Farmacéutica/métodos , Pirimidinas/síntesis química , Diseño de Fármacos , Haloperidol/química , Humanos , Concentración de Iones de Hidrógeno , Concentración 50 Inhibidora , Modelos Químicos , Enfermedad de Parkinson/terapia , Unión Proteica , Pirimidinas/química , Pirimidinas/farmacología , Receptor de Adenosina A1/química , Receptor de Adenosina A2A/química , Solubilidad , Relación Estructura-ActividadRESUMEN
4-Acetylamino-2-(3,5-dimethylpyrazol-1-yl)-pyrimidines bearing substituted pyridyl groups as C-6 substituents were prepared as selective adenosine hA2A receptor antagonists for the treatment of Parkinson's disease. The 5-methoxy-3-pyridyl derivative 6g (hA2A Ki 2.3 nM, hA1 Ki 190 nM) was orally active at 3 mg/kg in a rat HIC model but exposure was poor in nonrodent species, presumably due to poor aqueous solubility. Follow-on compound 16a (hA2A Ki 0.83 nM, hA1 Ki 130 nM), bearing a 6-(morpholin-4-yl)-2-pyridyl substituent at C-6, had improved solubility and was orally efficacious (3 mg/kg, HIC) but showed time-dependent cytochrome P450 3A4 inhibition, possibly related to morpholine ring metabolism. Compound 16j (hA2A Ki 0.44 nM, hA1 Ki 80 nM), bearing a 6-(4-methoxypiperidin-1-yl)-2-pyridyl substituent at C-6, was sparingly soluble but had good oral exposure in rodent and nonrodent species, had no cytochrome P450 or human ether-a-go-go related gene channel issues, and was orally efficacious at 1 mg/kg in HIC and at 3 mg/kg for potentiation of l-dopa-induced contralateral rotations in 6-hydroxydopamine-lesioned rats.
Asunto(s)
Antagonistas del Receptor de Adenosina A2 , Enfermedad de Parkinson/tratamiento farmacológico , Pirazoles/farmacología , Pirimidinas/farmacología , Animales , Catalepsia/inducido químicamente , Catalepsia/tratamiento farmacológico , Modelos Animales de Enfermedad , Diseño de Fármacos , Evaluación Preclínica de Medicamentos , Haloperidol , Humanos , Ligandos , Estructura Molecular , Pirazoles/síntesis química , Pirazoles/química , Pirimidinas/síntesis química , Pirimidinas/química , Ratas , Estereoisomerismo , Relación Estructura-ActividadRESUMEN
The discovery and synthesis of a series of (dimethoxyphenoxy)alkylamino acetamides as orexin-2 receptor antagonists from a small-molecule combinatorial library using a high-throughput calcium mobilization functional assay (HEK293-human OX2-R cell line) is described. Active compounds show a good correlation between high-throughput single concentration screening data and measured IC(50)s. Specific examples exhibit IC(50) values of approximately 20 nM using human orexin A as the peptide agonist for the orexin-2 receptor.
Asunto(s)
Acetamidas/síntesis química , Química Farmacéutica/métodos , Péptidos y Proteínas de Señalización Intracelular/química , Neuropéptidos/química , Receptores Acoplados a Proteínas G/antagonistas & inhibidores , Receptores de Neuropéptido/antagonistas & inhibidores , Acetamidas/química , Calcio/química , Línea Celular , Técnicas Químicas Combinatorias , Diseño de Fármacos , Humanos , Concentración 50 Inhibidora , Modelos Químicos , Mutación , Receptores de Orexina , Orexinas , TemperaturaRESUMEN
Antagonists of the corticotropin releasing factor (CRF or CRH) receptor have shown promise for the treatment of anxiety, depression, and irritable bowel syndrome. In the present article, medicinal chemistry developments surrounding small molecule CRF receptor antagonists are reviewed, focusing on publications and patents from mid-2004 through the first quarter of 2006. While the CRF type 2 receptor remains an intractable target, incremental progress has been made in the search for drug-like antagonists of the CRF type 1 receptor. Most recent work has not ventured far from previously-established pharmacophoric topologies. A common theme in recent patent disclosures is the addition of novel polar substituents to known heterocyclic core structures to reduce overall lipophilicity. New disclosures of pharmacokinetic (PK) data for several series of antagonists reveal that achieving appropriate PK remains a challenge for the field. The recent publication of selection patents and patents relating to salt and crystal forms of particular compounds suggests that several second generation compounds are nearing or have entered clinical development.
Asunto(s)
Ansiolíticos/química , Antidepresivos/química , Receptores de Hormona Liberadora de Corticotropina/antagonistas & inhibidores , Ansiolíticos/farmacocinética , Ansiolíticos/farmacología , Antidepresivos/farmacocinética , Antidepresivos/farmacología , Ansiedad/tratamiento farmacológico , Química Farmacéutica , Depresión/tratamiento farmacológico , Síndrome del Colon Irritable/tratamiento farmacológico , Relación Estructura-ActividadRESUMEN
A series of N-pyrimidinyl-2-phenoxyacetamide adenosine A(2A) antagonists is described. SAR studies led to compound 14 with excellent potency (K(i) = 0.4 nM), selectivity (A(1)/A(2A) > 100), and efficacy (MED 10 mg/kg p.o.) in the rat haloperidol-induced catalepsy model for Parkinson's disease.
Asunto(s)
Antagonistas del Receptor de Adenosina A2 , Antiparkinsonianos/síntesis química , Catalepsia/prevención & control , Enfermedad de Parkinson/fisiopatología , Fenoxiacetatos/síntesis química , Pirimidinas/síntesis química , Administración Oral , Animales , Antiparkinsonianos/farmacología , Catalepsia/inducido químicamente , Citocromo P-450 CYP2D6/metabolismo , Inhibidores del Citocromo P-450 CYP2D6 , Citocromo P-450 CYP3A , Inhibidores Enzimáticos del Citocromo P-450 , Sistema Enzimático del Citocromo P-450/metabolismo , Electrofisiología , Canales de Potasio Éter-A-Go-Go/antagonistas & inhibidores , Haloperidol/toxicidad , Humanos , Estructura Molecular , Fenoxiacetatos/química , Fenoxiacetatos/farmacología , Pirimidinas/química , Pirimidinas/farmacología , Ratas , Relación Estructura-ActividadRESUMEN
In this report, the design and synthesis of a series of pyrimidine based adenosine A(2A) antagonists are described. The strategy and outcome of expanding SAR exploration to attenuate hERG and improve selectivity over A(1) are discussed. Compound 33 exhibited excellent potency, selectivity over A(1), and reduced hERG liability.
Asunto(s)
Antagonistas del Receptor de Adenosina A2 , Proteínas de Unión al ADN/antagonistas & inhibidores , Pirimidinas/farmacología , Transactivadores/antagonistas & inhibidores , Línea Celular , Citocromo P-450 CYP3A/metabolismo , Inhibidores del Citocromo P-450 CYP3A , Diseño de Fármacos , Humanos , Cinética , Pirimidinas/síntesis química , Pirimidinas/química , Receptor de Adenosina A2A/metabolismo , Relación Estructura-Actividad , Regulador Transcripcional ERGRESUMEN
The synthesis and SAR studies of tricyclic imidazo[4,5-b]pyridin-2-ones as human corticotropin-releasing factor receptor (CRF(1)) antagonists are discussed herein. Compound 16g was identified as a functional antagonist that inhibited CRF-stimulated cyclic adenosine monophosphate production and CRF-induced adrenocorticotrophic hormone release. Pharmacokinetics studies in rats showed that 16g was orally bioavailable, had good brain penetration, and had a moderate half-life. In our effort to identify CRF(1) antagonists with improved pharmacokinetics properties, 16g exhibited a favorably lower volume of distribution.
Asunto(s)
Compuestos Heterocíclicos con 3 Anillos/síntesis química , Imidazoles/síntesis química , Piridinas/síntesis química , Receptores de Hormona Liberadora de Corticotropina/antagonistas & inhibidores , Administración Oral , Hormona Adrenocorticotrópica/sangre , Animales , Barrera Hematoencefálica/metabolismo , Células CHO , Hormona Liberadora de Corticotropina/farmacología , Cricetinae , Cricetulus , AMP Cíclico/antagonistas & inhibidores , AMP Cíclico/biosíntesis , Diseño de Fármacos , Compuestos Heterocíclicos con 3 Anillos/farmacocinética , Compuestos Heterocíclicos con 3 Anillos/farmacología , Humanos , Imidazoles/farmacocinética , Imidazoles/farmacología , Inyecciones Intravenosas , Masculino , Piridinas/farmacocinética , Piridinas/farmacología , Ensayo de Unión Radioligante , Ratas , Ratas Sprague-Dawley , Estereoisomerismo , Relación Estructura-ActividadRESUMEN
In a previous report we demonstrated that merging together key structural elements present in an AT(1) receptor antagonist (1, irbesartan) with key structural elements in a biphenylsulfonamide ET(A) receptor antagonist (2) followed by additional optimization provided compound 3 as a dual-action receptor antagonist (DARA), which potently blocked both AT(1) and ET(A) receptors. Described herein are our efforts directed toward improving both the pharmacokinetic profile as well as the AT(1) and ET(A) receptor potency of 3. Our efforts centered on modifying the 2'-side chain of 3 and examining the isoxazolylsulfonamide moiety in 3. This effort resulted in the discovery of 7 as a highly potent second-generation DARA. Compound 7 also showed substantially improved pharmacokinetic properties compared to 3. In rats, DARA 7 reduced blood pressure elevations caused by intravenous infusion of Ang II or big ET-1 to a greater extent and with longer duration than DARA 3 or AT(1) or ET(A) receptor antagonists alone. Compound 7 clearly demonstrated superiority over irbesartan (an AT(1) receptor antagonist) in the normal SHR model of hypertension in a dose-dependent manner, demonstrating the synergy of AT(1) and ET(A) receptor blockade in a single molecule.
Asunto(s)
Bloqueadores del Receptor Tipo 1 de Angiotensina II/química , Bloqueadores del Receptor Tipo 1 de Angiotensina II/farmacología , Antagonistas de los Receptores de la Endotelina A , Isoxazoles/química , Isoxazoles/farmacología , Receptor de Angiotensina Tipo 1/efectos de los fármacos , Sulfonamidas/química , Sulfonamidas/farmacología , Administración Oral , Angiotensina II/farmacología , Bloqueadores del Receptor Tipo 1 de Angiotensina II/farmacocinética , Animales , Antihipertensivos/química , Antihipertensivos/farmacología , Disponibilidad Biológica , Compuestos de Bifenilo/química , Compuestos de Bifenilo/farmacología , Perros , Humanos , Hipertensión/tratamiento farmacológico , Irbesartán , Isoxazoles/farmacocinética , Macaca fascicularis , Masculino , Ratas , Ratas Endogámicas SHR , Relación Estructura-Actividad , Sulfonamidas/farmacocinética , Tetrazoles/química , Tetrazoles/farmacologíaRESUMEN
Angiotensin II and endothelin-1 activate their respective AT(1) and ET(A) receptors on vascular smooth muscle cells, producing vasoconstriction, and both peptides are implicated in the pathogenesis of essential hypertension. Angiotensin II potentiates the production of endothelin, and conversely endothelin augments the synthesis of angiotensin II. Both AT(1) and ET(A) receptor antagonists lower blood pressure in hypertensive patients; thus, a combination AT(1)/ET(A) receptor antagonist may have greater efficacy and broader utility compared with each drug alone. By rational drug design a biphenyl ET(A) receptor blocker was modified to acquire AT(1) receptor antagonism. These compounds (C and D) decreased Sar-Ile-Angiotensin II binding to AT(1) receptors and endothelin-1 binding to ET(A) receptors, and compound C inhibited angiotensin II- and endothelin-1-mediated Ca(2+) transients. In rats compounds C and D reduced blood pressure elevations caused by intravenous infusion of angiotensin II or big endothelin-1. Compound C decreased blood pressure in Na(+)-depleted spontaneously hypertensive rats and in rats with mineralocorticoid hypertension. Compound D was more efficacious than AT(1) receptor antagonists at reducing blood pressure in spontaneously hypertensive rats, and its superiority was likely due to its partial blockade of ET(A) receptors. Therefore compounds C and D are novel agents for treating a broad spectrum of patients with essential hypertension and other cardiovascular diseases.
Asunto(s)
Antihipertensivos/uso terapéutico , Compuestos de Bifenilo/uso terapéutico , Presión Sanguínea/efectos de los fármacos , Hipertensión/tratamiento farmacológico , Oxazoles/uso terapéutico , Receptor de Angiotensina Tipo 1/metabolismo , Receptor de Endotelina A/metabolismo , Sulfonamidas/uso terapéutico , Bloqueadores del Receptor Tipo 1 de Angiotensina II , Animales , Antihipertensivos/farmacología , Compuestos de Bifenilo/farmacología , Calcio/metabolismo , Desoxicorticosterona , Modelos Animales de Enfermedad , Antagonistas de los Receptores de la Endotelina A , Humanos , Irbesartán , Losartán/uso terapéutico , Masculino , Oxazoles/farmacología , Ratas , Ratas Endogámicas SHR , Sodio/metabolismo , Sulfonamidas/farmacología , Tetrazoles/farmacología , Tetrazoles/uso terapéuticoRESUMEN
A series of 4'-[(imidazol-1-yl)methyl]biphenylsulfonamides has potent antagonist activity against both angiotensin II AT(1) and endothelin ET(A) receptors. Such dual-acting antagonists could have utility in the treatment of hypertension, heart failure, and other cardiovascular diseases in a broad patient population. Certain compounds in the present series are orally active in a rat model of angiotensin II-mediated hypertension.
Asunto(s)
Antagonistas de Receptores de Angiotensina , Compuestos de Bifenilo/síntesis química , Compuestos de Bifenilo/farmacología , Antagonistas de los Receptores de Endotelina , Sulfonamidas/síntesis química , Sulfonamidas/farmacología , Animales , Sitios de Unión/efectos de los fármacos , Presión Sanguínea/efectos de los fármacos , Células CACO-2 , Diseño de Fármacos , Humanos , Imidazoles/síntesis química , Imidazoles/farmacología , Indicadores y Reactivos , Masculino , Ratas , Ratas Sprague-Dawley , Receptor de Angiotensina Tipo 1 , Receptor de Endotelina A , Relación Estructura-ActividadRESUMEN
The construction of triazacyclopenta[cd]pentalene diesters 6 by the reaction of dihydropyrrole alpha-ketoesters 3 with acylated hydrazines was evaluated further as a potential central strategic step in the total syntheses of complex guanidine alkaloids such as palau'amine and styloguanidine. Successful cyclocondensations were realized with acid-stable 2,2,2-trichloroethyl carbazate and thiosemicarbazide, but not tert-butyl carbazate. The substituent on the pyrrolidine nitrogen can be alkoxycarbonyl, sulfonyl, or an N-alkyl-2-acylpyrrole group. Siloxy substitution at C1 of the alpha-ketoester side chain is also tolerated.