RESUMEN
ABBV-467 is a highly potent and selective MCL-1 inhibitor that was advanced to a phase I clinical trial for the treatment of multiple myeloma. Due to its large size and structural complexity, ABBV-467 is a challenging synthetic target. Herein, we describe the synthesis of ABBV-467 on a decagram scale, which enabled preclinical characterization. The strategy is convergent and stereoselective, featuring a hindered biaryl cross coupling, enantioselective hydrogenation, and conformationally preorganized macrocyclization by C-O bond formation as key steps.
Asunto(s)
Antineoplásicos , Proteína 1 de la Secuencia de Leucemia de Células Mieloides , Antineoplásicos/farmacología , Hidrogenación , Proteína 1 de la Secuencia de Leucemia de Células Mieloides/antagonistas & inhibidoresRESUMEN
We have investigated the SAR of a series of pyrimidinone-containing Cdc7 kinase inhibitors. A wide range of amine substitutions give potent compounds with activities (K(i)) less than 1nM. Kinase selectivity is reasonable and cytotoxicity corresponds to inhibition of MCM2 phosphorylation.
Asunto(s)
Proteínas de Ciclo Celular/antagonistas & inhibidores , Inhibidores de Proteínas Quinasas/química , Inhibidores de Proteínas Quinasas/farmacología , Proteínas Serina-Treonina Quinasas/antagonistas & inhibidores , Pirimidinonas/química , Pirimidinonas/farmacología , Aminas/química , Aminas/farmacología , Proteínas de Ciclo Celular/metabolismo , Línea Celular Tumoral , Humanos , Componente 2 del Complejo de Mantenimiento de Minicromosoma , Proteínas Nucleares/metabolismo , Fosforilación/efectos de los fármacos , Proteínas Serina-Treonina Quinasas/metabolismo , Relación Estructura-ActividadRESUMEN
SAR studies on a series of thiophene amide derivatives provided CB(2) receptor agonists. The activity of the compounds was characterized by radioligand binding determination, multiple functional assays, ADME, and pharmacokinetic studies. A representative compound with selectivity for CB(2) over CB(1) effectively produced analgesia in behavioral models of neuropathic, inflammatory, and postsurgical pain. Control experiments using a CB(2) antagonist demonstrated the efficacy in the pain models resulted from CB(2) agonism.
Asunto(s)
Amidas/síntesis química , Analgésicos/síntesis química , Hiperalgesia/tratamiento farmacológico , Neuralgia/tratamiento farmacológico , Receptor Cannabinoide CB2/agonistas , Tiofenos/síntesis química , Amidas/farmacocinética , Amidas/farmacología , Analgésicos/farmacocinética , Analgésicos/farmacología , Animales , Disponibilidad Biológica , Línea Celular Tumoral , Relación Dosis-Respuesta a Droga , Humanos , Hiperalgesia/metabolismo , Neuralgia/metabolismo , Ensayo de Unión Radioligante , Ratas , Ratas Sprague-Dawley , Receptor Cannabinoide CB1/metabolismo , Receptor Cannabinoide CB2/metabolismo , Relación Estructura-Actividad , Tiofenos/farmacocinética , Tiofenos/farmacologíaRESUMEN
Synthesis and biological evaluation of a novel class of substituted N-benzyl-1-(2,3-dichlorophenyl)-1H-tetrazol-5-amine derivatives resulted in the identification of potent P2X(7) antagonists. These compounds were assayed for activity at both the human and rat P2X(7) receptors. On the benzyl moiety, a variety of functional groups were tolerated, including both electron-withdrawing and electron-donating substituents. Ortho-substitution on the benzyl group provided the greatest potency. The ortho-substituted analogs showed approximately 2.5-fold greater potency at human compared to rat P2X(7) receptors. Compounds 12 and 38 displayed hP2X(7)pIC(50)s>7.8 with less than 2-fold difference in potency at the rP2X(7).
Asunto(s)
Aminas/síntesis química , Antagonistas del Receptor Purinérgico P2X/síntesis química , Antagonistas del Receptor Purinérgico P2X/farmacología , Tetrazoles/síntesis química , Aminas/química , Aminas/farmacología , Animales , Humanos , Concentración 50 Inhibidora , Estructura Molecular , Unión Proteica/efectos de los fármacos , Antagonistas del Receptor Purinérgico P2X/química , Ratas , Relación Estructura-Actividad , Tetrazoles/química , Tetrazoles/farmacologíaRESUMEN
Cyclin-dependent kinase 9 (CDK9) is a serine/threonine kinase involved in the regulation of transcription elongation. An inhibition of CDK9 downregulates a number of short-lived proteins responsible for tumor maintenance and survival, including the antiapoptotic BCL-2 family member MCL-1. As pan-CDK inhibitors under development have faced dosing and toxicity challenges in the clinical setting, we generated selective CDK9 inhibitors that could be amenable to an oral administration. Here, we report the lead optimization of a series of azaindole-based inhibitors. To overcome early challenges with promiscuity and cardiovascular toxicity, carboxylates were introduced into the pharmacophore en route to compounds such as 14 and 16. These CDK9 inhibitors demonstrated a reduced toxicity, adequate pharmacokinetic properties, and a robust in vivo efficacy in mice upon oral dosing.
RESUMEN
A novel series of aminotriazole-based P2X(7) antagonists was synthesized, and their structure-activity relationships (SAR) were investigated for activity at both human and rat P2X(7) receptors. Most compounds showed greater potency at the human receptor although several analogs were discovered with potent activity (pIC(50) > or = 7.5) at both human and rat P2X(7).
Asunto(s)
Antagonistas del Receptor Purinérgico P2 , Piridinas/síntesis química , Piridinas/farmacología , Proteínas Recombinantes/antagonistas & inhibidores , Triazoles/síntesis química , Triazoles/farmacología , Animales , Humanos , Técnicas In Vitro , Estructura Molecular , Ratas , Receptores Purinérgicos P2/metabolismo , Receptores Purinérgicos P2X7 , Proteínas Recombinantes/metabolismo , Relación Estructura-ActividadRESUMEN
Aided by molecular modeling, compounds with a pyrimidine-based tricyclic scaffold were designed and confirmed to inhibit Wee1 kinase. Structure-activity studies identified key pharmacophores at the aminoaryl and halo-benzene regions responsible for binding affinity with sub-nM K i values. The potent inhibitors demonstrated sub-µM activities in both functional and mechanism-based cellular assays and also possessed desirable pharmacokinetic profiles. The lead molecule, 31, showed oral efficacy in potentiating the antiproliferative activity of irinotecan, a cytotoxic agent, in a NCI-H1299 mouse xenograft model.
RESUMEN
A novel series of sulfone N-formylhydroxylamines (retrohydroxamates) have been investigated as matrix metalloproteinases (MMP) inhibitors. The substitution of the ether linkage of ABT-770 (5) with a sulfone group 13a led to a substantial increase in activity against MMP-9 but was accompanied by a loss of selectivity for inhibition of MMP-2 and -9 over MMP-1 and diminished oral exposure. Replacement of the biphenyl P1' substituent with a phenoxyphenyl group provided compounds that are highly selective for inhibition of MMP-2 and -9 over MMP-1. Optimization of the substituent adjacent to the retrohydroxamate center in this series led to the clinical candidate ABT-518 (6), a highly potent, selective, orally bioavailable MMP inhibitor that has been shown to significantly inhibit tumor growth in animal cancer models.
Asunto(s)
Antineoplásicos/síntesis química , Formamidas/síntesis química , Hidroxilaminas/síntesis química , Metaloendopeptidasas/antagonistas & inhibidores , Inhibidores de Proteasas/síntesis química , Administración Oral , Animales , Antineoplásicos/química , Antineoplásicos/farmacocinética , Antineoplásicos/farmacología , Disponibilidad Biológica , Línea Celular , Formamidas/química , Formamidas/farmacocinética , Formamidas/farmacología , Hidroxilaminas/química , Hidroxilaminas/farmacocinética , Hidroxilaminas/farmacología , Macaca fascicularis , Inhibidores de la Metaloproteinasa de la Matriz , Ratones , Inhibidores de Proteasas/química , Inhibidores de Proteasas/farmacocinética , Inhibidores de Proteasas/farmacología , Relación Estructura-Actividad , Factor de Necrosis Tumoral alfa/metabolismo , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
To investigate the role played by the unique pre-DFG residue Val 195 of Cdc7 kinase on the potency of azaindole-chloropyridines (1), a series of novel analogues with various chloro replacements were synthesized and evaluated for their inhibitory activity against Cdc7. X-ray cocrystallization using a surrogate protein, GSK3ß, and modeling studies confirmed the azaindole motif as the hinge binder. Weaker hydrophobic interactions with Met 134 and Val 195 by certain chloro replacements (e.g., H, methyl) led to reduced Cdc7 inhibition. Meanwhile, data from other replacements (e.g., F, O) indicated that loss of such hydrophobic interaction could be compensated by enhanced hydrogen bonding to Lys 90. Our findings not only provide an in-depth understanding of the pre-DFG residue as another viable position impacting kinase inhibition, they also expand the existing knowledge of ligand-Cdc7 binding.
RESUMEN
Structure-activity relationship (SAR) studies were conducted around early tetrazole-based leads 3 and 4. Replacements for the tetrazole core were investigated and the pendant benzyl substitution was reoptimized with a triazole isostere. Triazole-based P2X(7) antagonists were identified with similar potency to the lead compound 4 but with improved physiochemical properties. Compound 12 was active in a rat model of neuropathic pain.
Asunto(s)
Antagonistas del Receptor Purinérgico P2 , Triazoles/farmacología , Animales , Ratas , Receptores Purinérgicos P2X7 , Relación Estructura-Actividad , Triazoles/químicaRESUMEN
As part of a fully integrated and comprehensive strategy to discover novel antibacterial agents, NMR- and mass spectrometry-based affinity selection screens were performed to identify compounds that bind to protein targets uniquely found in bacteria and encoded by genes essential for microbial viability. A biphenyl acid lead series emerged from an NMR-based screen with the Haemophilus influenzae protein HI0065, a member of a family of probable ATP-binding proteins found exclusively in eubacteria. The structure-activity relationships developed around the NMR-derived biphenyl acid lead were consistent with on-target antibacterial activity as the Staphylococcus aureus antibacterial activity of the series correlated extremely well with binding affinity to HI0065, while the correlation of binding affinity with B-cell cytotoxicity was relatively poor. Although further studies are needed to conclusively establish the mode of action of the biphenyl series, these compounds represent novel leads that can serve as the basis for the development of novel antibacterial agents that appear to work via an unprecedented mechanism of action. Overall, these results support the genomics-driven hypothesis that targeting bacterial essential gene products that are not present in eukaryotic cells can identify novel antibacterial agents.
Asunto(s)
Adenosina Trifosfatasas/metabolismo , Antibacterianos/química , Proteínas Bacterianas/metabolismo , Química Farmacéutica/métodos , Haemophilus influenzae/metabolismo , Secuencia de Aminoácidos , Animales , Linfocitos B/metabolismo , Diseño de Fármacos , Genoma Bacteriano , Genómica , Espectroscopía de Resonancia Magnética , Espectrometría de Masas , Datos de Secuencia Molecular , Unión Proteica , Relación Estructura-ActividadRESUMEN
The D-Ala-D-Ala adding enzyme (MurF) from Streptococcus pneumoniae catalyzes the ATP-dependent formation of the UDP-MurNAc-pentapeptide, a critical component of the bacterial cell wall. MurF is a potential target for antibacterial design because it is unique to bacteria and performs an essential non-redundant function in the bacterial cell. The recent discovery and subsequent cocrystal structure determination of MurF in complex with a new class of inhibitors served as a catalyst to begin a medicinal chemistry program aimed at improving their potency. We report here a multidisciplinary approach to this effort that allowed for rapid generation of cocrystal structures, thereby providing the crystallographic information critical for driving the inhibitor optimization process. This effort resulted in the discovery of low-nanomolar inhibitors of this bacterial enzyme.
Asunto(s)
Inhibidores Enzimáticos/química , Péptido Sintasas/antagonistas & inhibidores , Relación Estructura-Actividad , Cristalización , Cristalografía por Rayos X , Inhibidores Enzimáticos/metabolismo , Concentración 50 Inhibidora , Ligandos , Espectroscopía de Resonancia Magnética , Modelos Moleculares , Péptido Sintasas/química , Péptido Sintasas/metabolismo , Especificidad por Sustrato , Sulfonamidas/química , Sulfonamidas/metabolismoRESUMEN
A series of imidazole-containing biphenyls was prepared and evaluated in vitro for inhibition of FTase and cellular Ras processing. Several of these analogues, such as 21, are potent inhibitors of FTase (<1nM), FTase/GGTase selective (>300-fold) and cellularly active (Asunto(s)
Transferasas Alquil y Aril/antagonistas & inhibidores
, Compuestos de Bifenilo/síntesis química
, Compuestos de Bifenilo/farmacología
, Inhibidores Enzimáticos/síntesis química
, Inhibidores Enzimáticos/farmacología
, Imidazoles/síntesis química
, Imidazoles/farmacología
, Células 3T3
, Animales
, Disponibilidad Biológica
, Compuestos de Bifenilo/farmacocinética
, Cristalografía por Rayos X
, Inhibidores Enzimáticos/farmacocinética
, Farnesiltransferasa
, Genes ras/efectos de los fármacos
, Semivida
, Imidazoles/farmacocinética
, Indicadores y Reactivos
, Ratones
, Modelos Moleculares
, Ratas
RESUMEN
A novel class of MurF inhibitors was discovered and structure-activity relationship studies have led to several potent compounds with IC(50)=22 approximately 70 nM. Unfortunately, none of these potent MurF inhibitors exhibited significant antibacterial activity even in the presence of bacterial cell permeabilizers.