RESUMEN
To improve the metabolic stability profile of BMS-741672 (1a), we undertook a structure-activity relationship study in our trisubstituted cyclohexylamine series. This ultimately led to the identification of 2d (BMS-753426) as a potent and orally bioavailable antagonist of CCR2. Compared to previous clinical candidate 1a, the tert-butyl amine 2d showed significant improvements in pharmacokinetic properties, with lower clearance and higher oral bioavailability. Furthermore, compound 2d exhibited improved affinity for CCR5 and good activity in models of both monocyte migration and multiple sclerosis in the hCCR2 knock-in mouse. The synthesis of 2d was facilitated by the development of a simplified approach to key intermediate (4R)-9b that deployed a stereoselective reductive amination which may prove to be of general interest.
RESUMEN
We encountered a dilemma in the course of studying a series of antagonists of the G-protein coupled receptor CC chemokine receptor-2 (CCR2): compounds with polar C3 side chains exhibited good ion channel selectivity but poor oral bioavailability, whereas compounds with lipophilic C3 side chains exhibited good oral bioavailability in preclinical species but poor ion channel selectivity. Attempts to solve this through the direct modulation of physicochemical properties failed. However, the installation of a protonation-dependent conformational switching mechanism resolved the problem because it enabled a highly selective and relatively polar molecule to access a small population of a conformer with lower polar surface area and higher membrane permeability. Optimization of the overall properties in this series yielded the CCR2 antagonist BMS-741672 (7), which embodied properties suitable for study in human clinical trials.
RESUMEN
We describe the hybridization of our previously reported acyclic and cyclic CC chemokine receptor 2 (CCR2) antagonists to lead to a new series of dual antagonists of CCR2 and CCR5. Installation of a γ-lactam as the spacer group and a quinazoline as a benzamide mimetic improved oral bioavailability markedly. These efforts led to the identification of 13d, a potent and orally bioavailable dual antagonist suitable for use in both murine and monkey models of inflammation.
RESUMEN
High-affinity, functionally potent, urea-based antagonists of CCR1 have been discovered. Modulation of PXR transactivation has revealed the selective and orally bioavailable CCR1 antagonist BMS-817399 (29), which entered clinical trials for the treatment of rheumatoid arthritis.
Asunto(s)
Artritis Reumatoide/tratamiento farmacológico , Descubrimiento de Drogas , Piperidinas/farmacología , Receptores CCR1/antagonistas & inhibidores , Urea/análogos & derivados , Valina/análogos & derivados , Animales , Disponibilidad Biológica , Ensayos Clínicos Fase II como Asunto , Células Hep G2 , Humanos , Masculino , Microsomas Hepáticos/metabolismo , Modelos Moleculares , Piperidinas/metabolismo , Piperidinas/farmacocinética , Piperidinas/uso terapéutico , Receptor X de Pregnano , Conformación Proteica , Receptores CCR1/química , Receptores CCR1/metabolismo , Receptores de Esteroides/metabolismo , Especificidad de la Especie , Urea/metabolismo , Urea/farmacocinética , Urea/farmacología , Urea/uso terapéutico , Valina/metabolismo , Valina/farmacocinética , Valina/farmacología , Valina/uso terapéuticoRESUMEN
A series of compounds which exhibited good human CCR1 binding and functional potency was modified resulting in the discovery of a novel series of high affinity, functionally potent antagonists of the CCR1 receptor. Issues of PXR activity, ion-channel potency, and poor metabolic stability were addressed by the addition of a hydroxyl group to an otherwise lipophilic area in the molecule resulting in the discovery of preclinical candidate BMS-457 for the treatment of rheumatoid arthritis.
Asunto(s)
Descubrimiento de Drogas , Piperidinas/farmacología , Receptores CCR1/antagonistas & inhibidores , Relación Dosis-Respuesta a Droga , Humanos , Estructura Molecular , Piperidinas/síntesis química , Piperidinas/química , Relación Estructura-ActividadRESUMEN
We report the synthesis of 3-phenylsulfonylmethyl cyclohexylaminobenzamides (4) as CCR2 inhibitors for the potential treatment of inflammatory diseases. Several of the compounds display nanomolar binding affinity for CCR2. The in vitro structure-activity relationships of 4 are described, and are also reconciled with those from the related 2-phenylsulfonylmethyl series.
Asunto(s)
Amidas/síntesis química , Aminobenzoatos/síntesis química , Modelos Moleculares , Receptores CCR2/antagonistas & inhibidores , Azufre/química , Amidas/química , Amidas/farmacología , Aminobenzoatos/química , Aminobenzoatos/farmacología , Animales , Ciclización , Humanos , Concentración 50 Inhibidora , Ratones , Microsomas/enzimología , Estructura Molecular , Unión Proteica/efectos de los fármacos , Ratas , Estereoisomerismo , Relación Estructura-Actividad , Especificidad por Sustrato , Azufre/farmacologíaRESUMEN
BACKGROUND: Prodrugs that exhibit ex vivo instability owing to high levels of esterases in rodent blood, plasma and serum present challenges in the accurate determination of drug exposure in samples from pharmacokinetic, pharmacokinetic/pharmacodynamic, efficacy and toxicology studies in drug discovery. Ensuring the stability of analytes in sample collection, handling, analysis and storage must be established for program progression. Current protocols for the stabilization of prodrugs include the immediate quenching of whole blood with acetonitrile or methanol to stop enzyme activity, or the addition of an esterase inhibitor such as phenylmethanesulfonyl fluoride to the blood collection tubes before serum or plasma is generated. Dried blood spots (DBS) sampling may offer an alternative prodrug stabilization method for sample collection and storage from rodent studies in drug discovery. RESULTS: Two different prodrugs of the same parent compound that were known to exhibit ex vivo instability in rodent blood were selected for the evaluation of DBS for analyte stabilization. Each prodrug was spiked separately into fresh rat EDTA whole blood and prepared three ways: from liquid whole blood, prepared and analyzed as lysate; from whole blood spotted onto Whatman 903(®) Protein Saver untreated cards (903 cards); and from whole blood spotted onto Whatman FTA(®) Elute Micro treated cards, currently known as DMPK-B cards (FTA cards). Samples were extracted by filtration-assisted protein precipitation at 0, 2, 5 and 24 h and 4, 7, 14 and 21 days after spiking and analyzed by UHPLC-MS/MS. CONCLUSIONS: For these two prodrugs, stability on DBS cards was observed in rat EDTA whole blood for at least 21 days at room temperature as determined by loss of prodrug and appearance of parent. The Whatman FTA Elute cards, treated with reagents that lyse cells, did not offer more stability for the investigated compounds than the Whatman 903 Protein Saver untreated cards.
Asunto(s)
Análisis Químico de la Sangre/métodos , Recolección de Muestras de Sangre/métodos , Descubrimiento de Drogas/métodos , Estabilidad de Medicamentos , Inhibidores Enzimáticos , Esterasas , Profármacos/química , Animales , Recolección de Muestras de Sangre/instrumentación , Cromatografía Líquida de Alta Presión , Desecación , Ácido Edético/química , Inhibidores Enzimáticos/farmacología , Esterasas/antagonistas & inhibidores , Esterasas/metabolismo , Indicadores y Reactivos/química , Profármacos/análisis , Profármacos/aislamiento & purificación , Ratas , Espectrometría de Masas en TándemRESUMEN
We describe the design, synthesis, and evaluation, of gamma-lactams as glycinamide replacements within a series of di- and trisubstituted cyclohexane CCR2 antagonists. The lactam-containing trisubstituted cyclohexanes proved to be more potent than the disubstituted analogs, as trisubstituted analog, lactam 13, displayed excellent activity (CCR2 binding IC(50)=1.0 nM and chemotaxis IC(50) = 0.5 nM) and improved metabolic stability over its parent glycinamide.
Asunto(s)
Ciclohexanos/farmacología , Glicina/análogos & derivados , Lactamas/química , Receptores CCR2/antagonistas & inhibidores , Animales , Quimiotaxis/efectos de los fármacos , Ciclohexanos/química , Glicina/química , RatonesRESUMEN
Conformational analysis of trans-1,2-disubstituted cyclohexane CCR3 antagonist 2 revealed that the cyclohexane linker could be replaced by an acyclic syn-alpha-methyl-beta-hydroxypropyl linker. Synthesis and biological evaluation of mono- and disubstituted propyl linkers support this conformational correlation. It was also found that the alpha-methyl group to the urea lowered protein binding and that the beta-hydroxyl group lowered affinity for CYP2D6. Ab initio calculations show that the alpha-methyl group governs the spatial orientation of three key functionalities within the molecule. alpha-Methyl-beta-hydroxypropyl urea 31 with a chemotaxis IC(50)=38 pM for eosinophils was chosen to enter clinical development for the treatment of asthma.
Asunto(s)
Quimiotaxis de Leucocito/efectos de los fármacos , Eosinófilos/efectos de los fármacos , Piperidinas/farmacología , Receptores CCR3/antagonistas & inhibidores , Urea/análogos & derivados , Administración Oral , Animales , Inhibidores Enzimáticos del Citocromo P-450 , Perros , Eosinófilos/citología , Enlace de Hidrógeno , Ratones , Conformación Molecular , Piperidinas/química , Piperidinas/farmacocinética , Ratas , Relación Estructura-Actividad , Urea/química , Urea/farmacocinética , Urea/farmacologíaRESUMEN
Conformational analysis of the 3-benzylpiperidine in CCR3 antagonist clinical candidate 1 (BMS-639623) predicts that the benzylpiperidine may be replaced by acyclic, conformationally stabilized, anti-1,2-disubstituted phenethyl- and phenpropylamines. Ab initio calculations, enantioselective syntheses, and evaluation in CCR3 binding and chemotaxis assays of anti-1-methyl-2-hydroxyphenethyl- and phenpropylamine-containing CCR3 antagonists support this conformational correlation.
Asunto(s)
Piperidinas/química , Piperidinas/farmacología , Receptores CCR3/antagonistas & inhibidores , Urea/análogos & derivados , Ciclización , Enlace de Hidrógeno , Conformación Molecular , Urea/química , Urea/farmacologíaRESUMEN
Starting with our previously described(20) class of CC chemokine receptor-3 (CCR3) antagonist, we improved the potency by replacing the phenyl linker of 1 with a cyclohexyl linker and by replacing the 4-benzylpiperidine with a 3-benzylpiperidine. The resulting compound, 32, is a potent and selective antagonist of CCR3. SAR studies showed that the 3-acetylphenyl urea of 32 could be replaced with heterocyclic ureas or heterocyclic-substituted phenyl ureas and still maintain the potency (inhibition of eotaxin-induced chemotaxis) of this class of compounds in the low-picomolar range (IC(50) = 10-60 pM), representing some of the most potent CCR3 antagonists reported to date. The potency of 32 for mouse CCR3 (chemotaxis IC(50) = 41 nM) and its oral bioavailability in mice (20% F ) were adequate to assess the efficacy in animal models of allergic airway inflammation. Oral administration of 32 reduced eosinophil recruitment into the lungs in a dose-dependent manner in these animal models. On the basis of its overall potency, selectivity, efficacy, and safety profile, the benzenesulfonate salt of 32, designated DPC168, entered phase I clinical trials.
Asunto(s)
Ciclohexanos/síntesis química , Compuestos de Fenilurea/síntesis química , Piperidinas/síntesis química , Receptores de Quimiocina/antagonistas & inhibidores , Animales , Disponibilidad Biológica , Células CHO , Células CACO-2 , Calcio/metabolismo , Quimiotaxis de Leucocito/efectos de los fármacos , Cricetinae , Ciclohexanos/química , Ciclohexanos/farmacología , Eosinófilos/efectos de los fármacos , Eosinófilos/fisiología , Femenino , Humanos , Hipersensibilidad/tratamiento farmacológico , Hipersensibilidad/inmunología , Técnicas In Vitro , Inflamación/tratamiento farmacológico , Masculino , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Permeabilidad , Compuestos de Fenilurea/química , Compuestos de Fenilurea/farmacología , Piperidinas/química , Piperidinas/farmacología , Receptores CCR3 , Estereoisomerismo , Relación Estructura-Actividad , Urea/análogos & derivados , Urea/síntesis química , Urea/química , Urea/farmacologíaRESUMEN
The synthesis and structure-activity relationships of N-arylalkylpiperidylmethyl ureas as antagonists of the CC chemokine receptor-3 (CCR3) are presented. These compounds displayed potent binding to the receptor as well as functional antagonism of eotaxin-elicited effects on eosinophils.
Asunto(s)
Piperidinas/síntesis química , Receptores de Quimiocina/antagonistas & inhibidores , Urea/síntesis química , Señalización del Calcio/efectos de los fármacos , Quimiocina CCL11 , Quimiocinas CC/farmacología , Interacciones Farmacológicas , Eosinófilos/efectos de los fármacos , Humanos , Concentración 50 Inhibidora , Piperidinas/farmacología , Unión Proteica , Receptores CCR3 , Relación Estructura-Actividad , Urea/farmacologíaRESUMEN
The discovery of novel and selective small molecule antagonists of the CC Chemokine Receptor-3 (CCR3) is presented. Simple conversion from a 4- to 3-benzylpiperidine gave improved selectivity for CCR3 over the serotonin 5HT(2A) receptor. Chiral resolution and exploration of mono- and disubstitution of the N-propylurea resulted in several 3-benzylpiperidine N-propylureas with CCR3 binding IC(50)s under 5 nM. Data from in vitro calcium mobilization and chemotaxis assays for these compounds ranged from high picomolar to low nanomolar EC(50)s and correlated well with antagonist binding IC(50)s.
Asunto(s)
Piperidinas/metabolismo , Receptores de Quimiocina/antagonistas & inhibidores , Receptores de Quimiocina/metabolismo , Urea/análogos & derivados , Urea/metabolismo , Animales , Células CHO , Bovinos , Cricetinae , Piperidinas/química , Unión Proteica/fisiología , Receptores CCR3 , Urea/químicaRESUMEN
Employing phenylmalonitrile dianion chemistry, a large number of analogues of MEK inhibitor lead SH053 (IC(50)=140 nM) were rapidly synthesized leading to single digit nM inhibitors, displaying submicromolar AP-1 transcription inhibition in COS-7 cells. Compound 41, exhibiting a MEK IC(50)=12 nM showed ip activity in a TPA-induced ear edema model with an ED(50)=5 mg/kg.
Asunto(s)
Butadienos/síntesis química , Química Farmacéutica/métodos , Inhibidores Enzimáticos/síntesis química , Quinasas de Proteína Quinasa Activadas por Mitógenos/antagonistas & inhibidores , Nitrilos/síntesis química , Animales , Células COS , Chlorocebus aethiops , Quinasas de Proteína Quinasa Activadas por Mitógenos/metabolismo , Relación Estructura-ActividadRESUMEN
CCR3 antagonist leads with IC(50) values in the microM range were converted into low nM binding compounds that displayed in vitro inhibition of human eosinophil chemotaxis induced by human eotaxin. In particular, 4-benzylpiperidin-1-yl-n-propylureas and erythro-3-(4-benzyl-2-(alpha-hydroxyalkyl)piperidin-1-yl)-n-propylureas (obtained via Beak reaction of N-BOC-4-benzylpiperidine) exhibited single digit nanomolar IC(50) values for CCR3.