RESUMEN
The introduction of chimeric antigen receptor T-cell (CAR-T cell) therapy has changed the treatment landscape of diffuse large B-cell lymphoma (DLBCL). However, the optimal treatment strategy after relapse after this therapy still needs to be elucidated. In this report, we describe the case of a 67-year-old male who relapsed after treatment with tisagenlecleucel as a third-line therapy. We present our approach to treatment after relapse, in which we tried to sustain the circulating chimeric antigen receptor T-cells. This is reflected by the kinetics of the chimeric antigen receptor T-cells during these treatments.
RESUMEN
KRAS is one of the most commonly mutated oncogenes in lung, colorectal, and pancreatic cancers. Recent clinical trials directly targeting KRAS G12C presented encouraging results for a large population of non-small cell lung cancer (NSCLC), but resistance to treatment is a concern. Continued exploration of new inhibitors and preclinical models is needed to address resistance mechanisms and improve duration of patient responses. To further enable the development of KRAS G12C inhibitors, we present a preclinical framework involving translational, non-invasive imaging modalities (CT and PET) and histopathology in a conventional xenograft model and a novel KRAS G12C knock-in mouse model of NSCLC. We utilized an in-house developed KRAS G12C inhibitor (Compound A) as a tool to demonstrate the value of this framework in studying in vivo pharmacokinetic/pharmacodynamic (PK/PD) relationship and anti-tumor efficacy. We characterized the Kras G12C-driven genetically engineered mouse model (GEMM) and identify tumor growth and signaling differences compared to its Kras G12D-driven counterpart. We also find that Compound A has comparable efficacy to sotorasib in the Kras G12C-driven lung tumors arising in the GEMM, but like observations in the clinic, some tumors inevitably progress on treatment. These findings establish a foundation for evaluating future KRAS G12C inhibitors that is not limited to xenograft studies and can be applied in a translationally relevant mouse model that mirrors human disease progression and resistance.
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Carcinoma de Pulmón de Células no Pequeñas , Neoplasias Pulmonares , Animales , Ratones , Humanos , Xenoinjertos , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Carcinoma de Pulmón de Células no Pequeñas/genética , Proteínas Proto-Oncogénicas p21(ras)/genética , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/genética , Trasplante Heterólogo , Modelos Animales de Enfermedad , MutaciónRESUMEN
The phosphoinositide 3-kinase (PI3K)/mammalian target of rapamycin (mTOR) signaling pathway is a frequently dysregulated pathway in human cancer, and PI3Kα is one of the most frequently mutated kinases in human cancer. A PI3Kα-selective inhibitor may provide the opportunity to spare patients the side effects associated with broader inhibition of the class I PI3K family. Here, we describe our efforts to discover a PI3Kα-selective inhibitor by applying structure-based drug design (SBDD) and computational analysis. A novel series of compounds, exemplified by 2,2-difluoroethyl (3S)-3-{[2'-amino-5-fluoro-2-(morpholin-4-yl)-4,5'-bipyrimidin-6-yl]amino}-3-(hydroxymethyl)pyrrolidine-1-carboxylate (1) (PF-06843195), with high PI3Kα potency and unique PI3K isoform and mTOR selectivity were discovered. We describe here the details of the design and synthesis program that lead to the discovery of 1.
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Diseño de Fármacos , Fosfatidilinositol 3-Quinasas/efectos de los fármacos , Inhibidores de las Quinasa Fosfoinosítidos-3/química , Inhibidores de las Quinasa Fosfoinosítidos-3/farmacología , Animales , Línea Celular , Cromatografía Líquida de Alta Presión/métodos , Cristalografía por Rayos X , Humanos , Enlace de Hidrógeno , Espectroscopía de Resonancia Magnética/métodos , Ratones , Estructura Molecular , Inhibidores de las Quinasa Fosfoinosítidos-3/síntesis química , Ratas , Espectrometría de Masa por Ionización de Electrospray/métodosRESUMEN
The novel coronavirus disease COVID-19 that emerged in 2019 is caused by the virus SARS CoV-2 and named for its close genetic similarity to SARS CoV-1 that caused severe acute respiratory syndrome (SARS) in 2002. Both SARS coronavirus genomes encode two overlapping large polyproteins, which are cleaved at specific sites by a 3C-like cysteine protease (3CLpro) in a post-translational processing step that is critical for coronavirus replication. The 3CLpro sequences for CoV-1 and CoV-2 viruses are 100% identical in the catalytic domain that carries out protein cleavage. A research effort that focused on the discovery of reversible and irreversible ketone-based inhibitors of SARS CoV-1 3CLpro employing ligand-protease structures solved by X-ray crystallography led to the identification of 3 and 4. Preclinical experiments reveal 4 (PF-00835231) as a potent inhibitor of CoV-2 3CLpro with suitable pharmaceutical properties to warrant further development as an intravenous treatment for COVID-19.
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Antivirales/farmacología , Proteasas 3C de Coronavirus/antagonistas & inhibidores , Cetonas/farmacología , Inhibidores de Proteasas/farmacología , SARS-CoV-2/efectos de los fármacos , Animales , Antivirales/síntesis química , Antivirales/metabolismo , Dominio Catalítico , Chlorocebus aethiops , Proteasas 3C de Coronavirus/química , Proteasas 3C de Coronavirus/metabolismo , Cristalografía por Rayos X , Humanos , Cetonas/síntesis química , Cetonas/metabolismo , Inhibidores de Proteasas/síntesis química , Inhibidores de Proteasas/metabolismo , Unión Proteica , Células Vero , Tratamiento Farmacológico de COVID-19RESUMEN
BACKGROUND: Treatment with anti-PD1 monoclonal antibodies improves the survival of metastatic melanoma patients but only a subgroup of patients benefits from durable disease control. Predictive biomarkers for durable benefit could improve the clinical management of patients. METHODS: Plasma samples were collected from patients receiving anti-PD1 therapy for ctDNA quantitative assessment of BRAFV600 and NRASQ61/G12/G13 mutations. RESULTS: After a median follow-up of 84 weeks 457 samples from 85 patients were analyzed. Patients with undetectable ctDNA at baseline had a better PFS (Hazard ratio (HR) = 0.47, median 26 weeks versus 9 weeks, p = 0.01) and OS (HR = 0.37, median not reached versus 21.3 weeks, p = 0.005) than patients with detectable ctDNA. Additionally, the HR for death was lower after the ctDNA level became undetectable during follow-up (adjusted HR: 0.16 (95% CI 0.07-0.36), p-value < 0.001). ctDNA levels > 500 copies/ml at baseline or week 3 were associated with poor clinical outcome. Patients progressive exclusively in the central nervous system (CNS) had undetectable ctDNA at baseline and at subsequent assessments. In multivariate analysis adjusted for LDH, CRP, ECOG and number of metastatic sites, the ctDNA remained significant for PFS and OS. A positive correlation was observed between ctDNA levels and total metabolic tumor volume (TMTV), number of metastatic sites and total tumor burden. CONCLUSIONS: Assessment of ctDNA baseline and during therapy was predictive for tumor response and clinical outcome in metastatic melanoma patients and reflected the tumor burden. ctDNA evaluation provided reliable complementary information during anti-PD1 antibody therapy.
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ADN Tumoral Circulante/sangre , Melanoma/sangre , Melanoma/terapia , Receptor de Muerte Celular Programada 1/antagonistas & inhibidores , Adulto , Anciano , Sistema Nervioso Central/patología , ADN Tumoral Circulante/genética , Costo de Enfermedad , Femenino , Estudios de Seguimiento , Humanos , Estimación de Kaplan-Meier , Masculino , Melanoma/genética , Melanoma/patología , Persona de Mediana Edad , Análisis Multivariante , Mutación/genética , Metástasis de la Neoplasia , Receptor de Muerte Celular Programada 1/metabolismo , Resultado del TratamientoRESUMEN
Monoclonal antibodies that block the programmed death-1 (anti-PD-1) or cytotoxic T-lymphocyte antigen-4 (CTLA-4) immune checkpoint receptors (pembrolizumab, nivolumab, ipilimumab, or the combination of nivolumab with ipilimumab) are approved treatment option for patients with advanced melanoma. Over half of all patients are refractory to these immunotherapies and are in need of alternative or complementary treatment options. Talimogene laherparepvec (T-VEC) is a first-in-class intralesionally delivered oncolytic immunotherapy, which has proven efficacy in the treatment of advanced melanoma. A proportion of patients treated with T-VEC will benefit from an abscopal response of noninjected metastases indicative of a systemic antitumor immune response elicited by the intratumoral injections. At present it remains unknown whether the systemic antitumor responses elicited by T-VEC are nonredundant with immune-checkpoint blockade. Recent data on potential synergy between T-VEC and both PD-1 and CTLA-4 blockade suggest that the mechanism of action may be complementary. We report on the successful treatment with intralesional T-VEC of two female patients with locoregionally advanced BRAF V600 wild-type melanoma who previously progressed on anti-PD-1 and anti-CTLA-4 inhibitors.
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Antineoplásicos Inmunológicos/efectos adversos , Resistencia a Antineoplásicos , Inmunoterapia/efectos adversos , Melanoma/terapia , Viroterapia Oncolítica , Terapia Recuperativa , Anciano , Femenino , Humanos , Inyecciones Intralesiones , Melanoma/inmunología , Melanoma/patología , PronósticoRESUMEN
Epidermal growth factor receptor (EGFR) and Kirsten rat sarcoma viral oncogene homolog (KRAS) oncogenic mutations are leading causes for lung cancer. Extensive drug discovery efforts targeting EGFR have led to the discovery and FDA approval of both reversible and covalent inhibitors. Second and third generation covalent inhibitors for EGFR have also been described, with the latter targeting specific emerging mutations. After decades of extensive effort, KRAS is widely regarded as an intractable therapeutic target; however, recent publications suggest covalent inhibition is a promising strategy to deliver inhibitors of the KRASG12C mutation.
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Anti-programmed death 1 (PD-1) monoclonal antibodies improve the survival of metastatic melanoma patients. Predictive or monitoring biomarkers for response to this therapy could improve the clinical management of these patients. To date, no established biomarkers are available for monitoring the response to immunotherapy. Tumor- specific mutations in circulating tumor DNA (ctDNA) such as BRAF and NRAS mutations for melanoma patients have been proposed for monitoring of immunotherapy response. We present seven illustrative cases for the use of ctDNA BRAF and NRAS mutations' monitoring in plasma. The cases described exemplify four distinct clinical benefit patterns: rapid and durable complete response (CR), early progression, followed by CR, CR followed by early progression after interrupting treatment and long-term disease stabilization. These representative cases suggest that comprehensive BRAF/NRAS ctDNA monitoring during anti-PD1 therapy is informative and can be of added value for the monitoring of melanoma patients gaining clinical benefit on anti-PD1 treatment. An important advantage of our approach is that using the cartridge system on the Idylla platform for mutation analysis, the results become available the same day 2 h after plasma collection. Therefore, in the future, the ctDNA level can be an element in the clinical management of the patients.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , ADN Tumoral Circulante/genética , GTP Fosfohidrolasas/genética , Melanoma/genética , Proteínas de la Membrana/genética , Mutación , Receptor de Muerte Celular Programada 1/antagonistas & inhibidores , Proteínas Proto-Oncogénicas B-raf/genética , Adulto , Anciano , Anciano de 80 o más Años , Anticuerpos Monoclonales/administración & dosificación , Anticuerpos Monoclonales Humanizados/administración & dosificación , Biomarcadores de Tumor/sangre , Biomarcadores de Tumor/genética , ADN Tumoral Circulante/sangre , ADN de Neoplasias/sangre , ADN de Neoplasias/genética , Progresión de la Enfermedad , Monitoreo de Drogas/métodos , Femenino , GTP Fosfohidrolasas/sangre , Humanos , Biopsia Líquida , Masculino , Melanoma/sangre , Melanoma/tratamiento farmacológico , Melanoma/patología , Proteínas de la Membrana/sangre , Persona de Mediana Edad , Nivolumab , Pronóstico , Proteínas Proto-Oncogénicas B-raf/sangre , Neoplasias Cutáneas/sangre , Neoplasias Cutáneas/tratamiento farmacológico , Neoplasias Cutáneas/genética , Neoplasias Cutáneas/secundarioRESUMEN
Patients with non-small cell lung cancers that have kinase-activating epidermal growth factor receptor (EGFR) mutations are highly responsive to first- and second-generation EGFR inhibitors. However, these patients often relapse due to a secondary, drug-resistant mutation in EGFR whereby the gatekeeper threonine is converted to methionine (T790M). Several third-generation EGFR inhibitors have been developed that irreversibly inactivate T790M-EGFR while sparing wild-type EGFR, thus reducing epithelium-based toxicities. Using chemical proteomics, we show here that individual T790M-EGFR inhibitors exhibit strikingly distinct off-target profiles in human cells. The FDA-approved drug osimertinib (AZD9291), in particular, was found to covalently modify cathepsins in cell and animal models, which correlated with lysosomal accumulation of the drug. Our findings thus show how chemical proteomics can be used to differentiate covalent kinase inhibitors based on global selectivity profiles in living systems and identify specific off-targets of these inhibitors that may affect drug activity and safety.
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Receptores ErbB/metabolismo , Inhibidores de Proteínas Quinasas/química , Proteoma/análisis , 5'-Nucleotidasa/química , 5'-Nucleotidasa/genética , 5'-Nucleotidasa/metabolismo , Acrilamidas , Compuestos de Anilina , Animales , Catepsinas/química , Catepsinas/metabolismo , Línea Celular Tumoral , Quinasa de Punto de Control 2/química , Quinasa de Punto de Control 2/genética , Quinasa de Punto de Control 2/metabolismo , Cisteína/química , Receptores ErbB/genética , Proteínas Ligadas a GPI/química , Proteínas Ligadas a GPI/genética , Proteínas Ligadas a GPI/metabolismo , Células HEK293 , Humanos , Hígado/metabolismo , Lisosomas/metabolismo , Ratones , Ratones Endogámicos C57BL , Mutagénesis Sitio-Dirigida , Piperazinas/química , Piperazinas/metabolismo , Inhibidores de Proteínas Quinasas/metabolismo , Proteómica , Rodaminas/química , Trasplante HeterólogoRESUMEN
Mutant epidermal growth factor receptor (EGFR) is a major driver of non-small-cell lung cancer (NSCLC). Marketed first generation inhibitors, such as erlotinib, effect a transient beneficial response in EGFR mutant NSCLC patients before resistance mechanisms render these inhibitors ineffective. Secondary oncogenic EGFR mutations account for approximately 50% of relapses, the most common being the gatekeeper T790M substitution that renders existing therapies ineffective. The discovery of PF-06459988 (1), an irreversible pyrrolopyrimidine inhibitor of EGFR T790M mutants, was recently disclosed.1 Herein, we describe our continued efforts to achieve potency across EGFR oncogenic mutations and improved kinome selectivity, resulting in the discovery of clinical candidate PF-06747775 (21), which provides potent EGFR activity against the four common mutants (exon 19 deletion (Del), L858R, and double mutants T790M/L858R and T790M/Del), selectivity over wild-type EGFR, and desirable ADME properties. Compound 21 is currently being evaluated in phase-I clinical trials of mutant EGFR driven NSCLC.
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Diseño de Fármacos , Receptores ErbB/antagonistas & inhibidores , Receptores ErbB/genética , Inhibidores de Proteínas Quinasas/química , Inhibidores de Proteínas Quinasas/farmacología , Pirrolidinas/química , Pirrolidinas/farmacología , Acrilamidas/química , Acrilamidas/farmacocinética , Acrilamidas/farmacología , Animales , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Carcinoma de Pulmón de Células no Pequeñas/genética , Línea Celular Tumoral , Perros , Halogenación , Humanos , Pulmón/efectos de los fármacos , Pulmón/metabolismo , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/genética , Ratones , Modelos Moleculares , Simulación del Acoplamiento Molecular , Mutación , Inhibidores de Proteínas Quinasas/farmacocinética , Pirrolidinas/farmacocinética , RatasRESUMEN
BACKGROUND: Patients with BRAFV600-mutant melanoma benefit from treatment with the combination of BRAF and MEK inhibitors, but resistance and disease progression develops in most patients. Preclinical studies and case studies have indicated that acquired resistance to BRAF inhibition can be reversible. We aimed to assess the anti-tumour activity of rechallenge with BRAF plus MEK inhibition in a prospective clinical trial. METHODS: In this open-label, single arm, dual-centre, phase 2 academic study in Belgium, patients aged 18 years or older with BRAFV600-mutant melanoma who had previously progressed on BRAF inhibitors (with or without MEK inhibitors) and were off-treatment for at least 12 weeks, were treated with dabrafenib 150 mg orally twice per day plus trametinib 2 mg orally once per day. The primary endpoint was the proportion of patients with investigator-assessed overall response at any time (defined as complete response or partial response according to Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 confirmed on two occasions, at least 28 days after the first response was recorded). Analyses were done in the intention-to-treat population. The study is ongoing but no longer recruiting patients. This trial is registered with ClinicalTrials.gov, number NCT02296996. FINDINGS: Between April 5, 2014, and Feb 2, 2016, 25 patients were enrolled and initiated treatment in our study. A partial response was documented in eight (32%) of 25 patients (95% CI 15-54; six patients had progressed on previous treatment with dabrafenib plus trametinib and two patients had progressed on previous BRAF inhibitor monotherapy). Stable disease was noted in ten patients (40%; 95% CI 21-61). Rechallenge with dabrafenib plus trametinib was well tolerated. There were no unexpected or grade 4 or 5 treatment-related adverse events. Grade 3 adverse events occurred in two patients (8%; panniculitis [n=1] and pyrexia [n=1]). Serious adverse events which occurred on study were one patient with an Addison crisis triggered by grade 2 pyrexia symptoms that resolved after discontinuation of dabrafenib and trametinib. No patients died as a result of study treatment. INTERPRETATION: Rechallenge with dabrafenib plus trametinib showed anti-tumour activity in patients who had previously progressed on BRAF inhibitors and as such, rechallenge represents a potential new treatment option for these patients. FUNDING: Vlaamse Liga Tegen Kanker, Novartis.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , MAP Quinasa Quinasa 1/antagonistas & inhibidores , Melanoma/tratamiento farmacológico , Mutación/genética , Inhibidores de Proteínas Quinasas/farmacología , Proteínas Proto-Oncogénicas B-raf/antagonistas & inhibidores , Proteínas Proto-Oncogénicas B-raf/genética , Neoplasias Cutáneas/tratamiento farmacológico , Adulto , Anciano , Progresión de la Enfermedad , Femenino , Estudios de Seguimiento , Humanos , Imidazoles/administración & dosificación , Metástasis Linfática , Masculino , Melanoma/genética , Melanoma/patología , Persona de Mediana Edad , Estadificación de Neoplasias , Oximas/administración & dosificación , Pronóstico , Piridonas/administración & dosificación , Pirimidinonas/administración & dosificación , Neoplasias Cutáneas/genética , Neoplasias Cutáneas/secundario , Tasa de SupervivenciaRESUMEN
First generation EGFR TKIs (gefitinib, erlotinib) provide significant clinical benefit for NSCLC cancer patients with oncogenic EGFR mutations. Ultimately, these patients' disease progresses, often driven by a second-site mutation in the EGFR kinase domain (T790M). Another liability of the first generation drugs is severe adverse events driven by inhibition of WT EGFR. As such, our goal was to develop a highly potent irreversible inhibitor with the largest selectivity ratio between the drug-resistant double mutants (L858R/T790M, Del/T790M) and WT EGFR. A unique approach to develop covalent inhibitors, optimization of reversible binding affinity, served as a cornerstone of this effort. PF-06459988 was discovered as a novel, third generation irreversible inhibitor, which demonstrates (i) high potency and specificity to the T790M-containing double mutant EGFRs, (ii) minimal intrinsic chemical reactivity of the electrophilic warhead, (iii) greatly reduced proteome reactivity relative to earlier irreversible EGFR inhibitors, and (iv) minimal activity against WT EGFR.
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Descubrimiento de Drogas , Receptores ErbB/antagonistas & inhibidores , Receptores ErbB/genética , Proteínas Mutantes/antagonistas & inhibidores , Inhibidores de Proteínas Quinasas/farmacología , Pirimidinas/farmacología , Pirroles/farmacología , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Carcinoma de Pulmón de Células no Pequeñas/genética , Relación Dosis-Respuesta a Droga , Humanos , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/genética , Modelos Moleculares , Estructura Molecular , Mutación , Inhibidores de Proteínas Quinasas/síntesis química , Inhibidores de Proteínas Quinasas/química , Pirimidinas/síntesis química , Pirimidinas/química , Pirroles/síntesis química , Pirroles/química , Relación Estructura-Actividad , Células Tumorales CultivadasRESUMEN
Inhibition of the Smoothened (Smo) represents a promising therapeutic strategy for treating malignant tumors that are dependent on the Hedgehog (Hh) signaling pathway. PF-5274857 is a novel Smo antagonist that specifically binds to Smo with a K(i) of 4.6 ± 1.1 nmol/L and completely blocks the transcriptional activity of the downstream gene Gli1 with an IC(50) of 2.7 ± 1.4 nmol/L in cells. This Smo antagonist showed robust antitumor activity in a mouse model of medulloblastoma with an in vivo IC(50) of 8.9 ± 2.6 nmol/L. The downregulation of Gli1 is closely linked to the tumor growth inhibition in patched(+/-) medulloblastoma mice. Mathematical analysis of the relationship between the drug's pharmacokinetics and Gli1 pharmacodynamics in patched(+/-) medulloblastoma tumor models yielded similar tumor and skin Gli1 IC(50) values, suggesting that skin can be used as a surrogate tissue for the measurement of tumor Gli1 levels. In addition, PF-5274857 was found to effectively penetrate the blood-brain barrier and inhibit Smo activity in the brain of primary medulloblastoma mice, resulting in improved animal survival rates. The brain permeability of PF-5274857 was also confirmed and quantified in nontumor-bearing preclinical species with an intact blood-brain barrier. PF-5274857 was orally available and metabolically stable in vivo. These findings suggest that PF-5274857 is a potentially attractive clinical candidate for the treatment of tumor types including brain tumors and brain metastasis driven by an activated Hh pathway.
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2,2'-Dipiridil/análogos & derivados , Proteínas Hedgehog/antagonistas & inhibidores , Proteínas Hedgehog/metabolismo , Meduloblastoma/tratamiento farmacológico , Piperazinas/farmacología , Receptores Acoplados a Proteínas G/antagonistas & inhibidores , 2,2'-Dipiridil/farmacología , Animales , Antineoplásicos , Barrera Hematoencefálica/efectos de los fármacos , Barrera Hematoencefálica/metabolismo , Línea Celular Tumoral , Células HEK293 , Humanos , Factores de Transcripción de Tipo Kruppel/genética , Factores de Transcripción de Tipo Kruppel/metabolismo , Meduloblastoma/patología , Ratones , Ratones SCID , Ratones Transgénicos , Receptores Patched , Ratas , Ratas Wistar , Receptores de Superficie Celular/genética , Receptores Acoplados a Proteínas G/metabolismo , Transducción de Señal/efectos de los fármacos , Receptor Smoothened , Proteína con Dedos de Zinc GLI1RESUMEN
The neutral endopeptidase inhibitor (2R)-2-[(1-{[(5-ethyl-1,3,4-thiadiazol-2-yl)amino]carbonyl}cyclopentyl)methyl]pentanoic acid 2 is metabolized to acyl glucuronide 3. Unprecedentedly, at pH 7.4, 3 does not undergo the O-acyl migration characteristic of acyl glucuronides but rapid, eliminative cyclization (t1/2 at 37 degrees C, 10.2 min) to glutarimide 4. Glucuronide 3 was synthesized efficiently via acylation of benzylglucuronate with N-benzyloxymethyl-protected 2. Glucuronide and imide reacted rapidly in aqueous solution, pH 7.4, with amino acids and glutathione to form stable amides and unstable thioesters. Imide 4 acylated eight lysine Nepsilon-amino groups of human serum albumin. Rapid cyclization of 3 was attributed to attack on the ester linkage by an unusually nucleophilic glutaramide NH (pKa in 2 = 9.76). N-propyl 3 was refractory to acyl migration and cyclization. This suggested a synthetic strategy for preparing analogues of 2 that form chemically stable acyl glucuronides.
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Glucurónidos/química , Neprilisina/antagonistas & inhibidores , Neprilisina/química , Ácidos Pentanoicos/química , Ácidos Pentanoicos/metabolismo , Piperidonas/síntesis química , Tiadiazoles/química , Tiadiazoles/síntesis química , Tiadiazoles/metabolismo , Animales , Ciclización , Humanos , Concentración de Iones de Hidrógeno , Hidrólisis , Masculino , Piperidonas/química , Piperidonas/farmacocinética , Ratas , Ratas Wistar , Albúmina Sérica/química , Estereoisomerismo , Tiadiazoles/farmacocinéticaRESUMEN
Female sexual arousal disorder (FSAD) is a highly prevalent sexual disorder affecting up to 40% of women. We describe herein our efforts to identify a selective neutral endopeptidase (NEP) inhibitor as a potential treatment for FSAD. The rationale for this approach, together with a description of the medicinal chemistry strategy, lead compounds, and SAR investigations are detailed. In particular, the strategy of starting with the clinically precedented selective NEP inhibitor, Candoxatrilat, and targeting low molecular weight and relatively polar mono-carboxylic acids is described. This led ultimately to the prototype development candidate R-13, for which detailed pharmacology and pharmacokinetic parameters are presented.(1)
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Ácidos Carbocíclicos/síntesis química , Amidas/síntesis química , Neprilisina/antagonistas & inhibidores , Ácidos Pentanoicos/síntesis química , Disfunciones Sexuales Psicológicas/tratamiento farmacológico , Tiadiazoles/síntesis química , Ácidos Carbocíclicos/farmacocinética , Ácidos Carbocíclicos/farmacología , Amidas/farmacocinética , Amidas/farmacología , Animales , Células CHO , Clítoris/irrigación sanguínea , Clítoris/efectos de los fármacos , Cricetinae , Cricetulus , Perros , Femenino , Humanos , Masculino , Ácidos Pentanoicos/farmacocinética , Ácidos Pentanoicos/farmacología , Piridinas/síntesis química , Piridinas/farmacocinética , Piridinas/farmacología , Conejos , Ratas , Proteínas Recombinantes/antagonistas & inhibidores , Flujo Sanguíneo Regional/efectos de los fármacos , Especificidad de la Especie , Estereoisomerismo , Relación Estructura-Actividad , Tiadiazoles/farmacocinética , Tiadiazoles/farmacología , Vagina/irrigación sanguínea , Vagina/efectos de los fármacosRESUMEN
A series of small molecule glutaramides were synthesized and evaluated for potency against canine and human neutral endopeptidase using target criteria of molecular weight <400 and log P between 2 and 4.5 to maximize the likelihood of achieving good oral absorption. The structure-activity relationship (SAR) investigations described in this paper led to the identification of an ethyl 1,3,4-thiadiazole glutaramide which demonstrated good neutral endopeptidase potency, selectivity and excellent oral absorption in the rat.