RESUMEN
BACKGROUND: Inhibition of PCSK9 (proprotein convertase subtilisin/kexin type 9)-low density lipoprotein receptor interaction with injectable monoclonal antibodies or small interfering RNA lowers plasma low density lipoprotein-cholesterol, but despite nearly 2 decades of effort, an oral inhibitor of PCSK9 is not available. Macrocyclic peptides represent a novel approach to target proteins traditionally considered intractable to small-molecule drug design. METHODS: Novel mRNA display screening technology was used to identify lead chemical matter, which was then optimized by applying structure-based drug design enabled by novel synthetic chemistry to identify macrocyclic peptide (MK-0616) with exquisite potency and selectivity for PCSK9. Following completion of nonclinical safety studies, MK-0616 was administered to healthy adult participants in a single rising-dose Phase 1 clinical trial designed to evaluate its safety, pharmacokinetics, and pharmacodynamics. In a multiple-dose trial in participants taking statins, MK-0616 was administered once daily for 14 days to characterize the safety, pharmacokinetics, and pharmacodynamics (change in low density lipoprotein cholesterol). RESULTS: MK-0616 displayed high affinity (Ki = 5pM) for PCSK9 in vitro and sufficient safety and oral bioavailability preclinically to enable advancement into the clinic. In Phase 1 clinical studies in healthy adults, single oral doses of MK-0616 were associated with >93% geometric mean reduction (95% CI, 84-103) of free, unbound plasma PCSK9; in participants on statin therapy, multiple-oral-dose regimens provided a maximum 61% geometric mean reduction (95% CI, 43-85) in low density lipoprotein cholesterol from baseline after 14 days of once-daily dosing of 20 mg MK-0616. CONCLUSIONS: This work validates the use of mRNA display technology for identification of novel oral therapeutic agents, exemplified by the identification of an oral PCSK9 inhibitor, which has the potential to be a highly effective cholesterol lowering therapy for patients in need.
Asunto(s)
Anticolesterolemiantes , Inhibidores de Hidroximetilglutaril-CoA Reductasas , Hipercolesterolemia , Adulto , Humanos , Anticolesterolemiantes/efectos adversos , Colesterol , LDL-Colesterol , Inhibidores de Hidroximetilglutaril-CoA Reductasas/uso terapéutico , Péptidos/uso terapéutico , Proproteína Convertasa 9/genética , Proproteína Convertasa 9/metabolismo , Receptores de LDL/genética , Receptores de LDL/metabolismoRESUMEN
Smoothened (Smo) antagonists are emerging as new therapies for the treatment of neoplasias with aberrantly reactivated hedgehog (Hh) signaling pathway. A novel series of 4-[3-(quinolin-2-yl)-1,2,4-oxadiazol-5-yl]piperazinyl ureas as smoothened antagonists was recently described, herein the series has been further optimized through the incorporation of a basic amine into the urea. This development resulted in identification of some exceptionally potent smoothened antagonists with low serum shifts, however, reductive ring opening on the 1,2,4-oxadiazole in rats limits the applicability of these compounds in in vivo studies.
Asunto(s)
Amidas/farmacología , Piperazinas/farmacología , Receptores Acoplados a Proteínas G/antagonistas & inhibidores , Amidas/síntesis química , Amidas/química , Estructura Molecular , Piperazinas/síntesis química , Piperazinas/química , Receptor Smoothened , Estereoisomerismo , Relación Estructura-ActividadRESUMEN
Proprotein convertase subtilisin-like/kexin type 9 (PCSK9) is a key regulator of plasma LDL-cholesterol (LDL-C) and a clinically validated target for the treatment of hypercholesterolemia and coronary artery disease. Starting from second-generation lead structures such as 2, we were able to refine these structures to obtain extremely potent bi- and tricyclic PCSK9 inhibitor peptides. Optimized molecules such as 44 demonstrated sufficient oral bioavailability to maintain therapeutic levels in rats and cynomolgus monkeys after dosing with an enabled formulation. We demonstrated target engagement and LDL lowering in cynomolgus monkeys essentially identical to those observed with the clinically approved, parenterally dosed antibodies. These molecules represent the first report of highly potent and orally bioavailable macrocyclic peptide PCSK9 inhibitors with overall profiles favorable for potential development as once-daily oral lipid-lowering agents. In this manuscript, we detail the design criteria and multiparameter optimization of this novel series of PCSK9 inhibitors.
Asunto(s)
Inhibidores de PCSK9/farmacología , Péptidos Cíclicos/farmacología , Administración Oral , Animales , Disponibilidad Biológica , Cristalografía por Rayos X , Macaca fascicularis , Estructura Molecular , Inhibidores de PCSK9/química , Inhibidores de PCSK9/farmacocinética , Péptidos Cíclicos/química , Péptidos Cíclicos/farmacocinética , Ratas , Relación Estructura-ActividadRESUMEN
We describe an extensive SAR study in the 6-[4-fluoro-3-(substituted)benzyl]-4,5-dimethylpyridazin-3(2H)-one series which led to the identification of potent PARP-1 inhibitors, capable of inhibiting the proliferation of BRCA-1 deficient cancer cells in the low nanomolar range, and displaying >100-fold selectivity over the BRCA wild type counterparts. The series of compounds was devoid of hERG channel activity, and CYP inhibition and induction liabilities. Several analogs were stable in rat and human liver microsomes and displayed moderate rat clearance, with urinary excretion of parent as the major route of elimination.
Asunto(s)
Proteína BRCA1/deficiencia , Piperazinas/síntesis química , Inhibidores de Poli(ADP-Ribosa) Polimerasas , Piridazinas/síntesis química , Animales , Proteína BRCA1/genética , Células HeLa , Humanos , Microsomas Hepáticos/efectos de los fármacos , Microsomas Hepáticos/enzimología , Piperazinas/metabolismo , Piperazinas/farmacología , Poli(ADP-Ribosa) Polimerasa-1 , Poli(ADP-Ribosa) Polimerasas/metabolismo , Piridazinas/metabolismo , Piridazinas/farmacología , RatasRESUMEN
Herein we describe the discovery of a novel series of pyrrolo[1,2-a]pyrazin-1(2H)-one PARP inhibitors. Optimization led to compounds that display excellent PARP-1 enzyme potency and inhibit the proliferation of BRCA deficient cells in the low double-digit nanomolar range showing excellent selectivity over BRCA proficient cancer cells.
Asunto(s)
Inhibidores de Poli(ADP-Ribosa) Polimerasas , Pirazinas/química , Pirazinas/metabolismo , Animales , Proteína BRCA1/deficiencia , Proteína BRCA1/metabolismo , Línea Celular Tumoral , Cristalografía por Rayos X , Células HeLa , Humanos , Indolizinas/química , Indolizinas/metabolismo , Microsomas Hepáticos/efectos de los fármacos , Microsomas Hepáticos/enzimología , Poli(ADP-Ribosa) Polimerasa-1 , Poli(ADP-Ribosa) Polimerasas/metabolismo , Unión Proteica/fisiología , Ratas , Relación Estructura-ActividadRESUMEN
Proprotein convertase subtilisin-like/kexin type 9 (PCSK9) is a key regulator of plasma LDL-cholesterol (LDL-C) and a clinically validated target for the treatment of hypercholesterolemia and coronary artery disease. In this paper, we describe a series of novel cyclic peptides derived from an mRNA display screen which inhibit the protein-protein interaction between PCSK9 and LDLR. Using a structure-based drug design approach, we were able to modify our original screening lead 2 to optimize the potency and metabolic stability and minimize the molecular weight to provide novel bicyclic next-generation PCSK9 inhibitor peptides such as 78. These next-generation peptides serve as a critical foundation for continued exploration of potential oral, once-a-day PCSK9 therapeutics for the treatment of cardiovascular disease.
Asunto(s)
Diseño de Fármacos , Inhibidores Enzimáticos/metabolismo , Inhibidores de PCSK9 , Proproteína Convertasa 9/metabolismo , ARN Mensajero/metabolismo , Animales , Células Cultivadas , Cristalografía por Rayos X/métodos , Inhibidores Enzimáticos/química , Femenino , Humanos , Macaca fascicularis , Masculino , Ratones , Ratones Endogámicos C57BL , Proproteína Convertasa 9/química , Estructura Secundaria de Proteína , Estructura Terciaria de Proteína , ARN Mensajero/química , Ratas , Ratas Wistar , Relación Estructura-ActividadRESUMEN
PARP inhibitors have been demonstrated to retard intracellular DNA repair and therefore sensitize tumor cells to cytotoxic agents or ionizing radiation. We report the identification of a novel class of PARP1 inhibitors, containing a pyrrolo moiety fused to a dihydroisoquinolinone, derived from virtual screening of the proprietary collection. SAR exploration around the nitrogen of the aminoethyl appendage chain of 1 led to compounds that displayed low nanomolar activity in a PARP1 enzymatic assay.
Asunto(s)
Inhibidores de Poli(ADP-Ribosa) Polimerasas , Quinolonas/química , Antineoplásicos/farmacología , Sitios de Unión , Química Farmacéutica/métodos , Cristalografía por Rayos X/métodos , Reparación del ADN , Diseño de Fármacos , Humanos , Enlace de Hidrógeno , Concentración 50 Inhibidora , Ligandos , Modelos Químicos , Polímeros/química , Relación Estructura-ActividadRESUMEN
We report the synthesis and biological evaluation of N-[(1-aryl-1H-indazol-5-yl)methyl]amide derivatives as Smoothened antagonists and inhibitors of the Hedgehog pathway. Identification of the lead structure 1 by HTS, followed by SAR study on the amide and aryl portions led to the discovery of antagonists with nanomolar activity.
Asunto(s)
Amidas/síntesis química , Indazoles/síntesis química , Receptores Acoplados a Proteínas G/antagonistas & inhibidores , Receptores Acoplados a Proteínas G/química , Amidas/farmacología , Catálisis , Línea Celular , Química Farmacéutica/métodos , Técnicas Químicas Combinatorias/métodos , Diseño de Fármacos , Evaluación Preclínica de Medicamentos , Humanos , Indazoles/farmacología , Concentración 50 Inhibidora , Modelos Químicos , Transducción de Señal , Receptor Smoothened , Relación Estructura-ActividadRESUMEN
A novel series of pyrazolo[1,5-a]quinazolin-5(4H)-one derivatives proved to be a potent class of PARP-1 inhibitors. An extensive SAR around the 3-position of pyrazole in the scaffold led to the discovery of amides derivatives as low nanomolar PARP-1 inhibitors.
Asunto(s)
Inhibidores Enzimáticos/síntesis química , Inhibidores de Poli(ADP-Ribosa) Polimerasas , Pirazoles/síntesis química , Amidas/química , Química Orgánica/métodos , Química Farmacéutica/métodos , Diseño de Fármacos , Evaluación Preclínica de Medicamentos , Inhibidores Enzimáticos/farmacología , Células HeLa , Humanos , Concentración 50 Inhibidora , Modelos Químicos , Estructura Molecular , Pirazoles/farmacología , Quinazolinonas/síntesis química , Quinazolinonas/farmacología , Relación Estructura-ActividadRESUMEN
Trifluoroacetylthiophene carboxamides have recently been reported to be class II HDAC inhibitors, with moderate selectivity. Exploration of replacements for the carboxamide with bioisosteric pentatomic heteroaromatic like 1,3,4-oxadiazoles, 1,2,4-oxadiazoles and 1,3-thiazoles, led to the discovery that 2-trifluoroacetylthiophene 1,3,4-oxadiazole derivatives are very potent low nanomolar HDAC4 inhibitors, highly selective over class I HDACs (HDAC 1 and 3), and moderately stable in HCT116 cell culture.