RESUMEN
BMS-931699 (lulizumab pegol), a domain antibody (dAb) conjugated with 40-kDa branched polyethylene glycol, is a human anti-CD28 receptor antagonist under development for the treatment of inflammatory and autoimmune diseases. In the present work, the minimal anticipated biologic effect level (MABEL) was determined for BMS-931699 by integrating all the available preclinical data. The relevance of the in vitro mixed lymphocyte reaction (MLR) assay to a whole blood CD28 receptor occupancy (RO) assessment, as well as the relationship between the CD28 RO and the inhibition of T-cell-dependent antibody response to keyhole limpet hemocyanin in vivo, was demonstrated through an integrated pharmacokinetic/pharmacodynamic analysis using anti-hCD28 dAb-001 (differing from BMS-931699 by two additional amino acids at the N-terminus) and a mouse surrogate. Based on this analysis, the EC10 value (0.32 nM) from the human MLR assay and the human plasma volume (0.04 l/kg) were employed to calculate the MABEL (0.01 mg) of BMS-931699 in humans, with a CD28 RO predicted to be ≤10%. The estimated MABEL dose was threefold higher than the value derived from the binding constant and twofold less than the MABEL converted from animal efficacy studies based on the body surface area. Furthermore, it was 2900-fold lower than the human equivalent dose derived from the no observed adverse effect level in monkeys (15 mg/kg/week for 5 doses, intravenous dosing) with a 10-fold safety factor applied. Therefore, the MABEL dose represented a sound approach to mitigate any potential risk in targeting CD28 and was successfully used as the first-in-human starting dose for BMS-931699.
Asunto(s)
Anticuerpos/farmacología , Antígenos CD28/antagonistas & inhibidores , Polietilenglicoles/farmacología , Polietilenglicoles/farmacocinética , Algoritmos , Animales , Superficie Corporal , Relación Dosis-Respuesta a Droga , Femenino , Hemocianinas/antagonistas & inhibidores , Humanos , Prueba de Cultivo Mixto de Linfocitos , Macaca fascicularis , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos DBA , Pruebas de Sensibilidad Microbiana , Monocitos/efectos de los fármacosRESUMEN
Targeting the CD28-CD80/86 pathway with an anti-CD28 antagonist is a promising alternative to current therapies for autoimmunity. However, attempts at generating conventional anti-CD28 mAbs lacking stimulatory activity has been challenging. In this study, we describe anti-human CD28 receptor antagonist domain Abs (dAbs) that are specific for human CD28. These dAbs are potent inhibitors of T cell activation, with an EC50 of 35 ± 14 ng/ml for inhibition of proliferation. The EC50 of 53 ± 11 ng/ml in an ex vivo CD28 receptor occupancy assay corresponds with in vitro functional activity, suggesting a direct correlation. The anti-CD28 dAb is equipotent in the inhibition of CD80- and CD86-mediated T cell proliferation and does not interfere with CTLA-4-mediated downmodulation of CD86 expression on APCs. The anti-CD28 dAbs are monomeric and do not demonstrate any evidence of agonism or costimulatory activity. In cynomolgus monkeys, the anti-CD28 dAb demonstrated pharmacodynamic activity, as measured by the inhibition of a T cell-dependent Ab response, without evidence of T cell depletion or cytokine release. Furthermore, there was a strong correlation between systemic exposure, duration, and extent of CD28 receptor occupancy, and pharmacodynamic activity. Taken together, these data support clinical evaluation of this novel anti-CD28 dAb for the treatment of autoimmune diseases.
Asunto(s)
Antígeno B7-1/inmunología , Antígeno B7-2/inmunología , Antígenos CD28/antagonistas & inhibidores , Antígenos CD28/inmunología , Linfocitos T/inmunología , Animales , Anticuerpos/inmunología , Células Presentadoras de Antígenos/inmunología , Enfermedades Autoinmunes/terapia , Antígeno CTLA-4/inmunología , Proliferación Celular , Humanos , Activación de Linfocitos/inmunología , Macaca fascicularisRESUMEN
Inosine monophosphate dehydrogenase (IMPDH), a key enzyme in the de novo synthesis of guanosine nucleotides, catalyzes the irreversible nicotinamide-adenine dinucleotide dependent oxidation of inosine-5'-monophosphate to xanthosine-5'-monophosphate. Mycophenolate Mofetil (MMF), a prodrug of mycophenolic acid, has clinical utility for the treatment of transplant rejection based on its inhibition of IMPDH. The overall clinical benefit of MMF is limited by what is generally believed to be compound-based, dose-limiting gastrointestinal (GI) toxicity that is related to its specific pharmacokinetic characteristics. Thus, development of an IMPDH inhibitor with a novel structure and a different pharmacokinetic profile may reduce the likelihood of GI toxicity and allow for increased efficacy. This article will detail the discovery and SAR leading to a novel and potent acridone-based IMPDH inhibitor 4m and its efficacy and GI tolerability when administered orally in a rat adjuvant arthritis model.
Asunto(s)
Acridinas/síntesis química , IMP Deshidrogenasa/antagonistas & inhibidores , Piperazinas/síntesis química , Acridinas/farmacología , Acridinas/toxicidad , Administración Oral , Animales , Artritis Experimental/tratamiento farmacológico , Artritis Reumatoide/tratamiento farmacológico , Disponibilidad Biológica , Línea Celular , Proliferación Celular , Tracto Gastrointestinal/efectos de los fármacos , Semivida , Humanos , Leucocitos Mononucleares/efectos de los fármacos , Macaca fascicularis , Masculino , Piperazinas/farmacología , Piperazinas/toxicidad , Ratas , Ratas Endogámicas Lew , Estereoisomerismo , Relación Estructura-ActividadRESUMEN
Inosine monophosphate dehydrogenase (IMPDH) is a key enzyme that is involved in the de novo synthesis of purine nucleotides. Novel 2-aminooxazoles were synthesized and tested for inhibition of IMPDH catalytic activity. Multiple analogues based on this chemotype were found to inhibit IMPDH with low nanomolar potency. One of the analogues (compound 23) showed excellent in vivo activity in the inhibition of antibody production in mice and in the adjuvant induced arthritis model in rats.
Asunto(s)
Inhibidores Enzimáticos/síntesis química , IMP Deshidrogenasa/antagonistas & inhibidores , Morfolinas/síntesis química , Ácido Micofenólico/análogos & derivados , Oxazoles/síntesis química , Animales , Formación de Anticuerpos/efectos de los fármacos , Artritis Experimental/tratamiento farmacológico , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/farmacología , Ensayo de Inmunoadsorción Enzimática , Masculino , Ratones , Ratones Endogámicos BALB C , Morfolinas/química , Morfolinas/farmacología , Ácido Micofenólico/farmacología , Oxazoles/química , Oxazoles/farmacología , Ratas , Ratas Endogámicas Lew , Relación Estructura-ActividadRESUMEN
A modified approach to the synthesis of 3-(oxazolyl-5-yl) indoles is reported. This method was applied to the synthesis of series of novel indole based inhibitors of inosine monophosphate dehydrogenase (IMPDH). The synthesis and the structure-activity relationships (SARs), derived from in vitro studies, for this new series of inhibitors is given.
Asunto(s)
IMP Deshidrogenasa/antagonistas & inhibidores , Indoles/farmacología , Sitios de Unión , Cianuros/química , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/farmacología , Humanos , Indoles/síntesis química , Activación de Linfocitos/efectos de los fármacos , Relación Estructura-Actividad , Linfocitos T/efectos de los fármacos , Células Tumorales CultivadasRESUMEN
A series of novel amide-based small molecule inhibitors of inosine monophosphate dehydrogenase is described. The synthesis and the structure-activity relationships (SARs) derived from in vitro studies are presented.
Asunto(s)
Diamida/química , Diamida/farmacología , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/farmacología , IMP Deshidrogenasa/antagonistas & inhibidores , Catálisis , Relación Estructura-ActividadRESUMEN
A series of novel small molecule inhibitors of inosine monophosphate dehydrogenase (IMPDH), based upon a 3-cyanoindole core, were explored. IMPDH catalyzes the rate determining step in guanine nucleotide biosynthesis and is a target for anticancer, immunosuppressive and antiviral therapy. The synthesis and the structure-activity relationships (SAR), derived from in vitro studies, for this new series of inhibitors is given.
Asunto(s)
Inhibidores Enzimáticos/farmacología , IMP Deshidrogenasa/antagonistas & inhibidores , Indoles/farmacología , Catálisis , Cinética , Relación Estructura-ActividadRESUMEN
A series of novel amide-based small molecule inhibitors of inosine monophosphate dehydrogenase (IMPDH) was explored. The synthesis and the structure-activity relationships (SARs) derived from in vitro studies are described.
Asunto(s)
Amidas/síntesis química , Amidas/farmacología , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/farmacología , IMP Deshidrogenasa/antagonistas & inhibidores , Antivirales/síntesis química , Antivirales/farmacología , Antivirales/toxicidad , Cristalografía por Rayos X , Inhibidores Enzimáticos/toxicidad , Enfermedades Gastrointestinales/inducido químicamente , Enfermedades Gastrointestinales/patología , Inmunosupresores/síntesis química , Inmunosupresores/farmacología , Inmunosupresores/toxicidad , Indicadores y Reactivos , Relación Estructura-ActividadRESUMEN
A series of novel guanidine-based small molecule inhibitors of inosine monophosphate dehydrogenase (IMPDH) was explored. IMPDH catalyzes the rate determining step in guanine nucleotide biosynthesis and is a target for anticancer, immunosuppressive and antiviral therapy. The synthesis and the structure-activity relationships (SARs), derived from in vitro studies, for this new series of inhibitors is given.
Asunto(s)
Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/farmacología , Guanidina/análogos & derivados , Guanidina/síntesis química , IMP Deshidrogenasa/antagonistas & inhibidores , Antivirales/síntesis química , Antivirales/farmacología , Cristalografía por Rayos X , Relación Dosis-Respuesta a Droga , Guanidina/farmacología , Humanos , Indicadores y Reactivos , Relación Estructura-ActividadRESUMEN
The development of a series of novel indole-based inhibitors of 5'-inosine monophosphate dehydrogenase (IMPDH) is described. Various hydrogen bond acceptors at C-3 of the indole were explored. The synthesis and the structure-activity relationships (SARs) derived from in vitro studies are outlined.
Asunto(s)
Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/farmacología , IMP Deshidrogenasa/antagonistas & inhibidores , Indoles/química , División Celular/efectos de los fármacos , Inhibidores Enzimáticos/química , Glucurónidos/metabolismo , Humanos , Enlace de Hidrógeno , Sistema Inmunológico/efectos de los fármacos , Isoenzimas/antagonistas & inhibidores , Mitógenos/farmacología , Quinolonas/síntesis química , Quinolonas/farmacología , Estereoisomerismo , Relación Estructura-ActividadRESUMEN
A series of heterocyclic replacements for the central diamide moiety of 1, a potent small molecule inhibitor of inosine monophosphate dehydrogenase (IMPDH) were explored The synthesis and the structure-activity relationships (SARs), derived from in vitro studies, for these new series of inhibitors is given.
Asunto(s)
Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/farmacología , Compuestos Heterocíclicos/síntesis química , Compuestos Heterocíclicos/farmacología , IMP Deshidrogenasa/antagonistas & inhibidores , Humanos , Técnicas In Vitro , Indicadores y Reactivos , Ligandos , Linfocitos/efectos de los fármacos , Linfocitos/metabolismo , Modelos Moleculares , Conformación Molecular , Estereoisomerismo , Relación Estructura-ActividadRESUMEN
A series of novel quinolone-based small molecule inhibitors of inosine monophosphate dehydrogenase (IMPDH) was explored. The synthesis and the structure-activity relationships (SARs) derived from in vitro studies are described.
Asunto(s)
Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/farmacología , IMP Deshidrogenasa/antagonistas & inhibidores , Quinolonas/síntesis química , Quinolonas/farmacología , División Celular/efectos de los fármacos , Células Cultivadas , Fenómenos Químicos , Química Física , Cristalografía por Rayos X , Humanos , Relación Estructura-Actividad , Linfocitos T/efectos de los fármacos , Linfocitos T/enzimologíaRESUMEN
The synthesis and the structure-activity relationships (SAR) of analogues derived from the introduction of basic residues on ring D of quinolone-based inhibitors of IMPDH are described. This led to the identification of compound 27 as a potent inhibitor of IMPDH with significantly improved aqueous solubility over the lead compound 1.
Asunto(s)
Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/farmacología , IMP Deshidrogenasa/antagonistas & inhibidores , Quinolonas/síntesis química , Quinolonas/farmacología , Humanos , Estereoisomerismo , Relación Estructura-ActividadRESUMEN
The first reported structure-activity relationships (SARs) about the N-[3-methoxy-4-(5-oxazolyl)phenyl moiety for a series of recently disclosed inosine monophosphate dehydrogenase (IMPDH) inhibitors are described. The syntheses and in vitro inhibitory values for IMPDH II, and T-cell proliferation (for select analogues) are given.
Asunto(s)
Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/farmacología , IMP Deshidrogenasa/antagonistas & inhibidores , Oxazoles/química , Oxazoles/farmacología , Animales , Carbamatos/química , Carbamatos/farmacología , Línea Celular , Cricetinae , Cricetulus , Concentración 50 Inhibidora , Activación de Linfocitos/efectos de los fármacos , Ácido Micofenólico/análogos & derivados , Ácido Micofenólico/farmacología , Oxazoles/síntesis química , Compuestos de Fenilurea/química , Compuestos de Fenilurea/farmacología , Relación Estructura-Actividad , Linfocitos T/efectos de los fármacos , Linfocitos T/fisiologíaRESUMEN
Screening of our in-house compound collection led to the discovery of 5-bromo-6-amino-2-isoquinoline 1 as a weak inhibitor of IMPDH. Subsequent optimization of 1 afforded a series of novel 2-isoquinolinoaminooxazole-based inhibitors, represented by 17, with single-digit nanomolar potency against the enzyme.
Asunto(s)
Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/farmacología , IMP Deshidrogenasa/antagonistas & inhibidores , Isoquinolinas/síntesis química , Isoquinolinas/farmacología , Oxazoles/síntesis química , Oxazoles/farmacología , Evaluación Preclínica de Medicamentos , Escherichia coli/enzimología , Humanos , NAD/metabolismo , Relación Estructura-ActividadRESUMEN
A series of novel triazine-based small molecule inhibitors (IV) of inosine monophosphate dehydrogenase was prepared. The synthesis and the structure-activity relationships (SAR) derived from in vitro studies are described.