RESUMEN
Plasmepsin X (PMX) is an essential aspartyl protease controlling malaria parasite egress and invasion of erythrocytes, development of functional liver merozoites (prophylactic activity), and blocking transmission to mosquitoes, making it a potential multistage drug target. We report the optimization of an aspartyl protease binding scaffold and the discovery of potent, orally active PMX inhibitors with in vivo antimalarial efficacy. Incorporation of safety evaluation early in the characterization of PMX inhibitors precluded compounds with a long human half-life (t1/2) to be developed. Optimization focused on improving the off-target safety profile led to the identification of UCB7362 that had an improved in vitro and in vivo safety profile but a shorter predicted human t1/2. UCB7362 is estimated to achieve 9â¯logâ¯10 unit reduction in asexual blood-stage parasites with once-daily dosing of 50 mg for 7 days. This work demonstrates the potential to deliver PMX inhibitors with in vivo efficacy to treat malaria.
Asunto(s)
Antimaláricos , Antagonistas del Ácido Fólico , Malaria , Animales , Humanos , Antimaláricos/farmacología , Antimaláricos/uso terapéutico , Plasmodium falciparum/metabolismo , Ácido Aspártico Endopeptidasas , Malaria/tratamiento farmacológicoRESUMEN
We present a comprehensive analysis of all ring systems (both heterocyclic and nonheterocyclic) in clinical trial compounds and FDA-approved drugs. We show 67% of small molecules in clinical trials comprise only ring systems found in marketed drugs, which mirrors previously published findings for newly approved drugs. We also show there are approximately 450â¯000 unique ring systems derived from 2.24 billion molecules currently available in synthesized chemical space, and molecules in clinical trials utilize only 0.1% of this available pool. Moreover, there are fewer ring systems in drugs compared with those in clinical trials, but this is balanced by the drug ring systems being reused more often. Furthermore, systematic changes of up to two atoms on existing drug and clinical trial ring systems give a set of 3902 future clinical trial ring systems, which are predicted to cover approximately 50% of the novel ring systems entering clinical trials.
RESUMEN
Over the last 10 years considerable progress has been made in the application of small molecules to modulating protein-protein interactions (PPIs), and the navigation from "undruggable" to a host of candidate molecules in clinical trials has been well-charted in recent, comprehensive reviews. Structure-based design has played an important role in this scientific journey, with three dimensional structures guiding medicinal chemistry efforts. However, the importance of two additional dimensions: movement and time is only now being realised, as increasing computing power, closely aligned with wet lab validation, is applied to the challenge. Protein dynamics are fundamental to biology and disease, and application to PPI drug discovery has massively widened the scope for new chemical entities to influence function from allosteric, and previously unreported, sites. In this forward-looking perspective we highlight exciting, new opportunities for small molecules to modulate disease biology, by adjusting the frequency profile of natural conformational sampling, through the stabilisation of clinically desired conformers of target proteins.
RESUMEN
Sulfones feature prominently in biologically active molecules and are key functional groups for organic synthesis. We report a mild, photoredox-catalyzed reaction for sulfonylation of aniline derivatives with sulfinate salts, and demonstrate the utility of the method by the late-stage functionalization of drugs. Key features of the method are the straightforward generation of sulfonyl radicals from bench-stable sulfinate salts and the use of simple aniline derivatives as convenient readily available coupling partners.
RESUMEN
Tackling PPIs, particularly by stabilizing clinically favored conformations of target proteins, with orally available, bona fide small molecules remains a significant but immensely worthwhile challenge for the pharmaceutical industry. Success may be more likely through the application of nature's learnings to build intrinsic rigidity into the design of clinical candidates.
Asunto(s)
Diseño de Fármacos , Dominios y Motivos de Interacción de Proteínas/efectos de los fármacos , Estabilidad Proteica/efectos de los fármacos , Proteínas/metabolismo , Bibliotecas de Moléculas Pequeñas/farmacología , Descubrimiento de Drogas , Humanos , Unión Proteica , Bibliotecas de Moléculas Pequeñas/químicaRESUMEN
Heteroaromatic nitriles are important compounds in drug discovery, both for their prevalence in the clinic and due to the diverse range of transformations they can undergo. As such, efficient and reliable methods to access them have the potential for far-reaching impact across synthetic chemistry and the biomedical sciences. Herein, we report an approach to heteroaromatic C-H cyanation through triflic anhydride activation, nucleophilic addition of cyanide, followed by elimination of trifluoromethanesulfinate to regenerate the cyanated heteroaromatic ring. This one-pot protocol is simple to perform, is applicable to a broad range of decorated 6-ring N-containing heterocycles, and has been shown to be suitable for late-stage functionalization of complex drug-like architectures.
RESUMEN
We have enumerated all linear combinations of ring systems from FDA approved drugs, up to three rings in length and up to four bonds linkers to give an in silico database of approximately 14 million molecules. This virtual library was compared with molecular databases of published and commercially available compounds to assess the prevalence of drug ring combinations in modern medicinal chemistry and to identify areas of under-represented, but clinically validated, chemical space. From the 10 trillion molecular comparisons, we found that less than 1% of the possible combinations of drug ring systems appear in commercially available libraries. This key observation highlights significant opportunities to design new fragment-like and lead-like libraries aimed at improving success rates and reducing risk in small molecule drug discovery, as, based on our previous analysis ( Taylor J. Med. Chem. 2014 , 57 , 5845 - 5849 ), approximately 70% of all new drugs are made up of only ring systems that have been used in existing drugs.
Asunto(s)
Aprobación de Drogas/legislación & jurisprudencia , Descubrimiento de Drogas , Bibliotecas de Moléculas Pequeñas , Estados Unidos , United States Food and Drug AdministrationRESUMEN
We have analyzed the rings, ring systems, and frameworks in drugs listed in the FDA Orange Book to understand the frequency, timelines, molecular property space, and the application of these rings in different therapeutic areas and target classes. This analysis shows that there are only 351 ring systems and 1197 frameworks in drugs that came onto the market before 2013. Furthermore, on average six new ring systems enter drug space each year and approximately 28% of new drugs contain a new ring system. Moreover, it is very unusual for a drug to contain more than one new ring system and the majority of the most frequently used ring systems (83%) were first used in drugs developed prior to 1983. These observations give insight into the chemical novelty of drugs and potentially efficient ways to assess compound libraries and develop compounds from hit identification to lead optimization and beyond.
Asunto(s)
Preparaciones Farmacéuticas/química , Bibliotecas de Moléculas Pequeñas/química , Algoritmos , Estructura Molecular , Bibliotecas de Moléculas Pequeñas/uso terapéuticoRESUMEN
The installation of geminal substitution at the C5' position of the carbosugar in our pyrimidine-derived hepatitis C inhibitor series is reported. SAR studies around the C5' position led to the installation of the dimethyl group as the optimal functionality. An improved route was subsequently designed to access these substitutions. Expanded SAR at the C2 amino position led to the utilization of C2 ethers. These compounds exhibited good potency, high selectivity, and excellent plasma exposure and bioavailability in rodent as well as in higher species.
Asunto(s)
Antivirales/síntesis química , Carbohidratos/química , Pirimidinas/química , Animales , Antivirales/química , Antivirales/farmacocinética , Disponibilidad Biológica , Perros , Semivida , Haplorrinos , Hepacivirus/efectos de los fármacos , Hepacivirus/metabolismo , Pirimidinas/síntesis química , Pirimidinas/farmacocinética , Ratas , Relación Estructura-Actividad , Replicación Viral/efectos de los fármacosRESUMEN
Introduction of a nitrogen atom into the benzene ring of a previously identified HCV replication (replicase) benzothiazole inhibitor 1, resulted in the discovery of the more potent pyridothiazole analogues 3. The potency and PK properties of the compounds were attenuated by the introductions of various functionalities at the R(1), R(2) or R(3) positions of the molecule (compound 3). Inhibitors 38 and 44 displayed excellent potency, selectivity (GAPDH/MTS CC(50)), PK parameters in all species studied, and cross genotype activity.
Asunto(s)
Antivirales/química , Antivirales/farmacología , Hepacivirus/efectos de los fármacos , Pirimidinas/química , Pirimidinas/farmacología , Replicación Viral/efectos de los fármacos , Animales , Antivirales/farmacocinética , Perros , Hepatitis C/tratamiento farmacológico , Hepatitis C/virología , Humanos , Pirimidinas/farmacocinética , Ratas , Relación Estructura-Actividad , Tiazoles/química , Tiazoles/farmacocinética , Tiazoles/farmacologíaRESUMEN
Introduction of nitrogen atom into the benzene ring of a previously identified HCV replication (replicase) benzofuran inhibitor 2, resulted in the discovery of the more potent pyridofuran analogue 5. Subsequent introduction of small alkyl and alkoxy ligands into the pyridine ring resulted in further improvements in replicon potency. Replacement of the 4-chloro moiety on the pyrimidine core with a methyl group, and concomitant monoalkylation of the C-2 amino moiety resulted in the identification of several inhibitors with desirable characteristics. Inhibitor 41, from the monosubstituted pyridofuran and inhibitor 50 from the disubstituted series displayed excellent potency, selectivity (GAPDH/MTS CC(50)) and PK parameters in all species studied, while the selectivity in the thymidine incorporation assay (DNA·CC(50)) was low.
Asunto(s)
Antivirales/química , Inhibidores Enzimáticos/química , Furanos/química , Hepacivirus/enzimología , Nucleósidos de Pirimidina/química , Pirimidinas/química , ARN Polimerasa Dependiente del ARN/antagonistas & inhibidores , Animales , Antivirales/síntesis química , Antivirales/farmacocinética , Benzofuranos/química , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/farmacocinética , Furanos/síntesis química , Furanos/farmacocinética , Semivida , Hígado/metabolismo , Nucleósidos de Pirimidina/síntesis química , Nucleósidos de Pirimidina/farmacocinética , Pirimidinas/síntesis química , Pirimidinas/farmacocinética , ARN Polimerasa Dependiente del ARN/metabolismo , Ratas , Relación Estructura-Actividad , Replicación Viral/efectos de los fármacosRESUMEN
Based on a previously identified HCV replication (replicase) inhibitor 1, SAR efforts were conducted around the pyrimidine core to improve the potency and pharmacokinetic profile of the inhibitors. A benzothiazole moiety was found to be the optimal substituent at the pyrimidine 5-position. Due to potential reactivity concern, the 4-chloro residue was replaced by a methyl group with some loss in potency and enhanced rat in vivo profile. Extensive investigations at the C-2 position resulted in identification of compound 16 that demonstrated very good replicon potency, selectivity and rodent plasma/target organ concentration. Inhibitor 16 also demonstrated good plasma levels and oral bioavailability in dogs, while monkey exposure was rather low. Chemistry optimization towards a practical route to install the benzothiazole moiety resulted in an efficient direct C-H arylation protocol.
Asunto(s)
Antivirales/química , Benzotiazoles/química , Hepacivirus/efectos de los fármacos , Pirimidinas/química , Replicación Viral/efectos de los fármacos , Animales , Perros , Haplorrinos , Hepacivirus/fisiología , Metilación , Roedores , Especificidad de la EspecieRESUMEN
Cyclic hydroxyamidines were designed and validated as isosteric replacements of the amide functionality. Compounds with these structural motifs were found to be metabolically stable and to possess highly desirable pharmacokinetic profiles. These designs were applied in the identification of γ-secretase modulators leading to highly efficacious agents for reduction of central nervous system Aß(42) in various animal models.
Asunto(s)
Amidinas/síntesis química , Secretasas de la Proteína Precursora del Amiloide/metabolismo , Oxadiazoles/síntesis química , Oxazinas/síntesis química , Amidinas/farmacocinética , Amidinas/farmacología , Péptidos beta-Amiloides/metabolismo , Animales , Encéfalo/metabolismo , Perros , Células HEK293 , Humanos , Macaca fascicularis , Masculino , Oxadiazoles/farmacocinética , Oxadiazoles/farmacología , Oxazinas/farmacocinética , Oxazinas/farmacología , Fragmentos de Péptidos/metabolismo , Ratas , Estereoisomerismo , Relación Estructura-ActividadRESUMEN
Hepatitis C virus (HCV) infects an estimated 170 million individuals worldwide, and the current standard of care, a combination of pegylated interferon alpha and ribavirin, is efficacious in achieving sustained viral response in ~50% of treated patients. Novel therapies under investigation include the use of nucleoside analog inhibitors of the viral RNA-dependent RNA polymerase. NM283, a 3'-valyl ester prodrug of 2'-C-methylcytidine, has demonstrated antiviral efficacy in HCV-infected patients (N. Afdhal et al., J. Hepatol. 46[Suppl. 1]:S5, 2007; N. Afdhal et al., J. Hepatol. 44[Suppl. 2]:S19, 2006). One approach to increase the antiviral efficacy of 2'-C-methylcytidine is to increase the concentration of the active inhibitory species, the 5'-triphosphate, in infected hepatocytes. HepDirect prodrug technology can increase intracellular concentrations of a nucleoside triphosphate in hepatocytes by introducing the nucleoside monophosphate into the cell, bypassing the initial kinase step that is often rate limiting. Screening for 2'-C-methylcytidine triphosphate levels in rat liver after oral dosing identified 1-[3,5-difluorophenyl]-1,3-propandiol as an efficient prodrug modification. To determine antiviral efficacy in vivo, the prodrug was administered separately via oral and intravenous dosing to two HCV-infected chimpanzees. Circulating viral loads declined by ~1.4 log(10) IU/ml and by >3.6 log(10) IU/ml after oral and intravenous dosing, respectively. The viral loads rebounded after the end of dosing to predose levels. The results indicate that a robust antiviral response can be achieved upon administration of the prodrug.
Asunto(s)
Citidina/análogos & derivados , Hepacivirus/efectos de los fármacos , Hepatitis C/tratamiento farmacológico , Profármacos/administración & dosificación , Animales , Antivirales/administración & dosificación , Antivirales/farmacología , Antivirales/uso terapéutico , Citidina/administración & dosificación , Citidina/farmacología , Citidina/uso terapéutico , Citidina Monofosfato/administración & dosificación , Citidina Monofosfato/análogos & derivados , Citidina Monofosfato/farmacología , Citidina Monofosfato/uso terapéutico , Femenino , Hepatitis C/virología , Hepatocitos/metabolismo , Macaca mulatta , Masculino , Pan troglodytes , Profármacos/farmacología , Profármacos/uso terapéutico , Nucleósidos de Pirimidina/administración & dosificación , Nucleósidos de Pirimidina/farmacología , Nucleósidos de Pirimidina/uso terapéutico , Ratas , Ratas Sprague-Dawley , Carga Viral/efectos de los fármacosRESUMEN
Efforts to develop novel, interferon-sparing therapies for treatment of chronic hepatitis C (HCV) infection are contingent on the ability of combination therapies consisting of direct antiviral inhibitors to achieve a sustained virologic response. This work demonstrates a proof of concept that coadministration of the nucleoside analogue MK-0608 with the protease inhibitor MK-7009, both of which produced robust viral load declines as monotherapy, to an HCV-infected chimpanzee can achieve a cure of infection.
Asunto(s)
Antivirales/administración & dosificación , Hepacivirus/efectos de los fármacos , Hepatitis C Crónica/tratamiento farmacológico , Indoles/administración & dosificación , Pan troglodytes/virología , Tubercidina/análogos & derivados , Carga Viral/efectos de los fármacos , Animales , Antivirales/farmacología , Antivirales/uso terapéutico , Ciclopropanos , Relación Dosis-Respuesta a Droga , Esquema de Medicación , Quimioterapia Combinada , Hepacivirus/enzimología , Hepacivirus/fisiología , Hepatitis C Crónica/virología , Indoles/farmacología , Indoles/uso terapéutico , Isoindoles , Lactamas Macrocíclicas , Leucina/análogos & derivados , Prolina/análogos & derivados , Inhibidores de Proteasas/administración & dosificación , Inhibidores de Proteasas/farmacología , Inhibidores de Proteasas/uso terapéutico , Sulfonamidas , Resultado del Tratamiento , Tubercidina/administración & dosificación , Tubercidina/farmacología , Tubercidina/uso terapéutico , Proteínas no Estructurales Virales/antagonistas & inhibidoresRESUMEN
The application of a phosphoramidate prodrug approach to 2'-C-methylcytidine (NM107), the first nucleoside inhibitor of the hepatitis C virus (HCV) NS5B polymerase, is reported. 2'-C-Methylcytidine, as its valyl ester prodrug (NM283), was efficacious in reducing the viral load in patients infected with HCV. Several of the phosphoramidates prepared demonstrated a 10- to 200-fold superior potency with respect to the parent nucleoside in the cell-based replicon assay. This is due to higher levels of 2'-C-methylcytidine triphosphate in the cells. These prodrugs are efficiently activated and converted to the triphosphate in hepatocytes of several species. Our SAR studies ultimately led to compounds that gave high levels of NTP in hamster and rat liver after subcutaneous dosing and that were devoid of the toxic phenol moiety usually found in ProTides.
Asunto(s)
Amidas/metabolismo , Amidas/uso terapéutico , Antivirales/metabolismo , Citidina/análogos & derivados , Hepatitis C/tratamiento farmacológico , Ácidos Fosfóricos/metabolismo , Ácidos Fosfóricos/uso terapéutico , Profármacos/metabolismo , Profármacos/uso terapéutico , Amidas/farmacología , Amidas/toxicidad , Animales , Antivirales/farmacología , Antivirales/uso terapéutico , Antivirales/toxicidad , Línea Celular , Citidina/metabolismo , Citidina/farmacología , Citidina/uso terapéutico , Citidina/toxicidad , Hepacivirus/efectos de los fármacos , Hepacivirus/fisiología , Hepatocitos/efectos de los fármacos , Hepatocitos/metabolismo , Hepatocitos/virología , Humanos , Ácidos Fosfóricos/farmacología , Ácidos Fosfóricos/toxicidad , Polifosfatos/metabolismo , Profármacos/farmacología , Profármacos/toxicidad , Relación Estructura-Actividad , Replicación Viral/efectos de los fármacosRESUMEN
Extremely potent very late antigen-4 (VLA-4) antagonists with picomolar, whole blood activity and slow dissociation rates were discovered by incorporating an amino substituent on the proline fragment of the initial lead structure. This level of potency against the unactivated form of VLA-4 was shown to be sufficient to overcome the poor pharmacokinetic profiles typical of this class of VLA-4 antagonists, and sustained activity as measured by receptor occupancy was achieved in preclinical species after oral dosing.
Asunto(s)
Integrina alfa4beta1/antagonistas & inhibidores , Niacinamida/análogos & derivados , Fenilalanina/análogos & derivados , Administración Oral , Animales , Citocromo P-450 CYP3A , Inhibidores del Citocromo P-450 CYP3A , Perros , Humanos , Concentración 50 Inhibidora , Niacinamida/síntesis química , Niacinamida/farmacocinética , Niacinamida/farmacología , Fenilalanina/administración & dosificación , Fenilalanina/síntesis química , Fenilalanina/farmacocinética , Fenilalanina/farmacología , RatasRESUMEN
A series of novel 1-aminocyclopentyl-3-carboxyamides incorporating substituted tetrahydropyran moieties have been synthesized and subsequently evaluated for their antagonistic activity against the human CCR2 receptor. Among them analog 59 was found to posses potent antagonistic activity.
Asunto(s)
Química Farmacéutica/métodos , Receptores CCR2/antagonistas & inhibidores , Receptores CCR2/química , Administración Oral , Animales , Quimiotaxis , Perros , Diseño de Fármacos , Humanos , Concentración 50 Inhibidora , Macaca mulatta , Modelos Químicos , Estructura Molecular , Ratas , Ratas Sprague-Dawley , Relación Estructura-ActividadRESUMEN
Platensimycin (1) displays antibacterial activity due to its inhibition of the elongation condensing enzyme (FabF), a novel mode of action that could potentially lead to a breakthrough in developing a new generation of antibiotics. The medicinal chemistry efforts were focused on the modification of the enone moiety of platensimycin and several analogs showed significant activity against FabF and possess antibacterial activity.
Asunto(s)
3-Oxoacil-(Proteína Transportadora de Acil) Sintasa/antagonistas & inhibidores , Adamantano/síntesis química , Aminobenzoatos/síntesis química , Anilidas/síntesis química , Antibacterianos/síntesis química , Proteínas Bacterianas/antagonistas & inhibidores , Química Farmacéutica/métodos , 3-Oxoacil-(Proteína Transportadora de Acil) Sintasa/química , Adamantano/farmacología , Aminobenzoatos/farmacología , Anilidas/farmacología , Antibacterianos/farmacología , Proteínas Bacterianas/química , Cristalografía por Rayos X/métodos , Diseño de Fármacos , Farmacorresistencia Microbiana , Enterococcus faecalis/metabolismo , Concentración 50 Inhibidora , Meticilina/farmacología , Pruebas de Sensibilidad Microbiana , Modelos Químicos , Estructura Molecular , Streptomyces/metabolismo , Relación Estructura-ActividadRESUMEN
Hepatitis C virus (HCV) infects an estimated 170 million individuals worldwide and is associated with an increased incidence of liver fibrosis, cirrhosis, and hepatocellular carcinoma. Currently approved therapies to treat HCV infection consist of combinations of pegylated alpha interferon and ribavirin which result in a sustained viral response in 40 to 60% of patients. Efforts to develop improved therapies include the development of direct inhibitors of virally encoded enzymes such as the viral RNA-dependent RNA polymerase. A nucleoside analog, 2'-C-methyl-7-deaza-adenosine (MK-0608), has been shown to inhibit viral RNA replication in the subgenomic HCV genotype 1b replicon, with a 50% effective concentration (EC(50)) of 0.3 microM (EC(90) = 1.3 microM). To determine efficacy in vivo, MK-0608 was administered to HCV-infected chimpanzees, resulting in dose- and time-dependent decreases in plasma viral loads. In separate experiments, chimpanzees dosed for 7 days with MK-0608 at 0.2 and 2 mg per kg of body weight per day by intravenous administration experienced average reductions in viral load of 1.0 and >5 log(10) IU/ml, respectively. Two other HCV-infected chimpanzees received daily doses of 1 mg MK-0608 per kg via oral administration. After 37 days of oral dosing, one chimpanzee with a high starting viral load experienced a reduction in viral load of 4.6 log(10), and the viral load in the other chimpanzee fell below the limit of quantification (LOQ) of the HCV TaqMan assay (20 IU/ml). Importantly, viral load remained below the LOQ throughout the duration of dosing and for at least 12 days after dosing ended. The results demonstrate a robust antiviral effect on the administration of MK-0608 to HCV-infected chimpanzees.