RESUMEN
A HTS screen for CCR1 antagonists afforded a novel sub-micromolar hit 5 containing a pyrazole core. In this report the design, optimization, and SAR of novel CCR1 antagonists based on a pyrazole core motif is presented. Optimization led to the advanced candidate compounds (S)-16q and (S)-16r with 250-fold improved CCR1 potency, excellent off-target selectivity and attractive drug-like properties.
Asunto(s)
Amidas/farmacología , Descubrimiento de Drogas , Pirazoles/farmacología , Receptores CCR1/antagonistas & inhibidores , Amidas/química , Relación Dosis-Respuesta a Droga , Humanos , Estructura Molecular , Pirazoles/química , Receptores CCR1/metabolismo , Relación Estructura-ActividadRESUMEN
The COVID-19 pandemic highlights the ongoing risk of zoonotic transmission of coronaviruses to global health. To prepare for future pandemics, it is essential to develop effective antivirals targeting a broad range of coronaviruses. Targeting the essential and clinically validated coronavirus main protease (Mpro), we constructed a structurally diverse Mpro panel by clustering all known coronavirus sequences by Mpro active site sequence similarity. Through screening, we identified a potent covalent inhibitor that engaged the catalytic cysteine of SARS-CoV-2 Mpro and used structure-based medicinal chemistry to develop compounds in the pyrazolopyrimidine sulfone series that exhibit submicromolar activity against multiple Mpro homologues. Additionally, we solved the first X-ray cocrystal structure of Mpro from the human-infecting OC43 coronavirus, providing insights into potency differences among compound-target pairs. Overall, the chemical compounds described in this study serve as starting points for the development of antivirals with broad-spectrum activity, enhancing our preparedness for emerging human-infecting coronaviruses.
Asunto(s)
Antivirales , Proteasas 3C de Coronavirus , SARS-CoV-2 , Humanos , SARS-CoV-2/efectos de los fármacos , SARS-CoV-2/enzimología , Proteasas 3C de Coronavirus/antagonistas & inhibidores , Proteasas 3C de Coronavirus/metabolismo , Antivirales/farmacología , Antivirales/química , Cristalografía por Rayos X , Tratamiento Farmacológico de COVID-19 , Relación Estructura-Actividad , COVID-19/virología , COVID-19/epidemiología , Inhibidores de Proteasa de Coronavirus/farmacología , Inhibidores de Proteasa de Coronavirus/química , Coronavirus Humano OC43/efectos de los fármacos , Dominio Catalítico , Modelos Moleculares , Inhibidores de Proteasas/farmacología , Inhibidores de Proteasas/química , Pandemias , Preparación para una PandemiaRESUMEN
Diarrhoeal disease caused by Cryptosporidium is a major cause of morbidity and mortality in young and malnourished children from low- and middle-income countries, with no vaccine or effective treatment. Here we describe the discovery of EDI048, a Cryptosporidium PI(4)K inhibitor, designed to be active at the infection site in the gastrointestinal tract and undergo rapid metabolism in the liver. By using mutational analysis and crystal structure, we show that EDI048 binds to highly conserved amino acid residues in the ATP-binding site. EDI048 is orally efficacious in an immunocompromised mouse model despite negligible circulating concentrations, thus demonstrating that gastrointestinal exposure is necessary and sufficient for efficacy. In neonatal calves, a clinical model of cryptosporidiosis, EDI048 treatment resulted in rapid resolution of diarrhoea and significant reduction in faecal oocyst shedding. Safety and pharmacological studies demonstrated predictable metabolism and low systemic exposure of EDI048, providing a substantial safety margin required for a paediatric indication. EDI048 is a promising clinical candidate for the treatment of life-threatening paediatric cryptosporidiosis.
RESUMEN
Millions who live in Latin America and sub-Saharan Africa are at risk of trypanosomatid infections, which cause Chagas disease and human African trypanosomiasis (HAT). Improved HAT treatments are available, but Chagas disease therapies rely on two nitroheterocycles, which suffer from lengthy drug regimens and safety concerns that cause frequent treatment discontinuation. We performed phenotypic screening against trypanosomes and identified a class of cyanotriazoles (CTs) with potent trypanocidal activity both in vitro and in mouse models of Chagas disease and HAT. Cryo-electron microscopy approaches confirmed that CT compounds acted through selective, irreversible inhibition of trypanosomal topoisomerase II by stabilizing double-stranded DNA:enzyme cleavage complexes. These findings suggest a potential approach toward successful therapeutics for the treatment of Chagas disease.
Asunto(s)
Enfermedad de Chagas , Inhibidores de Topoisomerasa II , Triazoles , Trypanosoma , Tripanosomiasis Africana , Animales , Humanos , Ratones , Enfermedad de Chagas/tratamiento farmacológico , Microscopía por Crioelectrón , ADN-Topoisomerasas de Tipo II/metabolismo , Trypanosoma/efectos de los fármacos , Inhibidores de Topoisomerasa II/química , Inhibidores de Topoisomerasa II/farmacología , Inhibidores de Topoisomerasa II/uso terapéutico , Triazoles/química , Triazoles/farmacología , Triazoles/uso terapéutico , Tripanosomiasis Africana/tratamiento farmacológico , Evaluación Preclínica de MedicamentosRESUMEN
Human African Trypanosomiasis (HAT) is a vector-borne disease caused by kinetoplastid parasites of the Trypanosoma genus. The disease proceeds in two stages, with a hemolymphatic blood stage and a meningo-encephalic brain stage. In the latter stage, the parasite causes irreversible damage to the brain leading to sleep cycle disruption and is fatal if untreated. An orally bioavailable treatment is highly desirable. In this study, we present a brain-penetrant, parasite-selective 20S proteasome inhibitor that was rapidly optimized from an HTS singleton hit to drug candidate compound 7 that showed cure in a stage II mouse efficacy model. Here, we describe hit expansion and lead optimization campaign guided by cryo-electron microscopy and an in silico model to predict the brain-to-plasma partition coefficient Kp as an important parameter to prioritize compounds for synthesis. The model combined with in vitro and in vivo experiments allowed us to advance compounds with favorable unbound brain-to-plasma ratios (Kp,uu) to cure a CNS disease such as HAT.
Asunto(s)
Quinolinas , Trypanosoma , Tripanosomiasis Africana , Animales , Microscopía por Crioelectrón , Modelos Animales de Enfermedad , Humanos , Ratones , Inhibidores de Proteasoma/farmacología , Inhibidores de Proteasoma/uso terapéutico , Quinolinas/farmacología , Quinolinas/uso terapéutico , Tripanosomiasis Africana/tratamiento farmacológico , Tripanosomiasis Africana/parasitologíaRESUMEN
A series of 5-aryl-2-amino-imidazothiadiazole (ITD) derivatives were identified by a phenotype-based high-throughput screening using a blood stage Plasmodium falciparum (Pf) growth inhibition assay. A lead optimization program focused on improving antiplasmodium potency, selectivity against human kinases, and absorption, distribution, metabolism, excretion, and toxicity properties and extended pharmacological profiles culminated in the identification of INE963 (1), which demonstrates potent cellular activity against Pf 3D7 (EC50 = 0.006 µM) and achieves "artemisinin-like" kill kinetics in vitro with a parasite clearance time of <24 h. A single dose of 30 mg/kg is fully curative in the Pf-humanized severe combined immunodeficient mouse model. INE963 (1) also exhibits a high barrier to resistance in drug selection studies and a long half-life (T1/2) across species. These properties suggest the significant potential for INE963 (1) to provide a curative therapy for uncomplicated malaria with short dosing regimens. For these reasons, INE963 (1) was progressed through GLP toxicology studies and is now undergoing Ph1 clinical trials.
Asunto(s)
Antimaláricos , Antagonistas del Ácido Fólico , Malaria Falciparum , Malaria , Animales , Antimaláricos/farmacología , Antimaláricos/uso terapéutico , Antagonistas del Ácido Fólico/uso terapéutico , Malaria/tratamiento farmacológico , Malaria Falciparum/tratamiento farmacológico , Ratones , Ratones SCID , Plasmodium falciparumRESUMEN
Dengue virus (DENV) is a mosquito-borne flavivirus that poses a threat to public health, yet no antiviral drug is available. We performed a high-throughput phenotypic screen using the Novartis compound library and identified candidate chemical inhibitors of DENV. This chemical series was optimized to improve properties such as anti-DENV potency and solubility. The lead compound, NITD-688, showed strong potency against all four serotypes of DENV and demonstrated excellent oral efficacy in infected AG129 mice. There was a 1.44-log reduction in viremia when mice were treated orally at 30 milligrams per kilogram twice daily for 3 days starting at the time of infection. NITD-688 treatment also resulted in a 1.16-log reduction in viremia when mice were treated 48 hours after infection. Selection of resistance mutations and binding studies with recombinant proteins indicated that the nonstructural protein 4B is the target of NITD-688. Pharmacokinetic studies in rats and dogs showed a long elimination half-life and good oral bioavailability. Extensive in vitro safety profiling along with exploratory rat and dog toxicology studies showed that NITD-688 was well tolerated after 7-day repeat dosing, demonstrating that NITD-688 may be a promising preclinical candidate for the treatment of dengue.
Asunto(s)
Virus del Dengue , Dengue , Animales , Antivirales/uso terapéutico , Dengue/tratamiento farmacológico , Perros , Ratones , Modelos Animales , Ratas , SerogrupoRESUMEN
We have been exploring the potential of 5-HT(2B) antagonists as a therapy for chronic heart failure. To assess the potential of this therapeutic approach, we sought compounds possessing the following attributes: (a) potent and selective antagonism of the 5-HT(2B) receptor, (b) low impact of serum proteins on potency, and (c) desirable pharmacokinetic properties. This Letter describes our investigation of a biphenyl benzimidazole class of compounds that resulted in 5-HT(2B) antagonists possessing the above attributes. Improving potency in a human serum albumin shift assay proved to be the most significant SAR discovery.
Asunto(s)
Receptor de Serotonina 5-HT2B/metabolismo , Antagonistas del Receptor de Serotonina 5-HT2 , Antagonistas de la Serotonina/química , Antagonistas de la Serotonina/farmacocinética , Animales , Sitios de Unión , Masculino , Relación Estructura-Actividad Cuantitativa , Ratas , Ratas Sprague-Dawley , Ratas Wistar , Receptor de Serotonina 5-HT2B/química , Antagonistas de la Serotonina/clasificaciónRESUMEN
High-throughput screening is routinely employed as a method for the identification of novel hit structures. Large numbers of active compounds are typically procured in this way and must undergo a rigorous validation process. This process is described in detail for a collection of screening hits identified as inhibitors of IkappaB kinase-beta (IKKbeta), a key regulatory enzyme in the nuclear factor-kappaB (NF-kappaB) pathway. From these studies, a promising hit series was selected. Subsequent lead generation activities included the development of a pharmacophore hypothesis and structure-activity relationship (SAR) for the hit series. This led to the exploration of related scaffolds offering additional opportunities, and the various structural classes were comparatively evaluated for enzyme inhibition, selectivity, and drug-like properties. A novel lead series of thienopyridines was thereby established, and this series advanced into lead optimization for further development.
Asunto(s)
Quinasa I-kappa B/antagonistas & inhibidores , Quinasa I-kappa B/química , Modelos Moleculares , Piridinas/síntesis química , Oxazoles/síntesis química , Oxazoles/química , Piridinas/química , Relación Estructura-ActividadRESUMEN
Benzimidazole 1 was identified as a selective inhibitor of ITK by high throughput screening. Hit-to-lead studies defined the SAR at all three substituents. Reversing the amide linkage at C6 led to 16, with a fivefold improvement of potency. This enhancement is rationalized by the conformational preference of the substituent. A model for the binding of the benzimidazoles to the ATP-binding site of ITK is proposed.
Asunto(s)
Bencimidazoles/química , Química Farmacéutica/métodos , Inhibidores de Proteínas Quinasas/síntesis química , Proteínas Tirosina Quinasas/antagonistas & inhibidores , Adenosina Trifosfato/química , Bencimidazoles/síntesis química , Sitios de Unión , Evaluación Preclínica de Medicamentos/métodos , Inhibidores Enzimáticos/farmacología , Humanos , Enlace de Hidrógeno , Concentración 50 Inhibidora , Modelos Químicos , Unión Proteica , Inhibidores de Proteínas Quinasas/química , Relación Estructura-ActividadRESUMEN
A new class of benzimidazolone p38 MAP kinase inhibitors was discovered through high-throughput screening. X-ray crystallographic data of the lead molecule with p38 were used to design analogues with improved binding affinity and potency in a cell assay of LPS-induced TNFalpha production. Herein, we report the SAR of this new class of p38 inhibitors.
Asunto(s)
Bencimidazoles/farmacología , Inhibidores Enzimáticos/farmacología , Proteínas Quinasas p38 Activadas por Mitógenos/antagonistas & inhibidores , Proteínas Quinasas p38 Activadas por Mitógenos/química , Bencimidazoles/síntesis química , Cristalografía por Rayos X , Inhibidores Enzimáticos/síntesis química , Modelos Moleculares , Conformación Molecular , Conformación Proteica , Relación Estructura-ActividadRESUMEN
A series of prolyl-1-piperazinylacetic acid and prolyl-4-piperidinylacetic acid derivatives were synthesized and evaluated for their activity as VLA-4 antagonists. Of 22 compounds synthesized, 19 compounds showed potent activity with low nanomolar IC50 values. In addition, the representative compounds 11o and 11p with a hydroxy group in the pyrrolidine ring showed moderate plasma clearance in rats (11o, 30 ml/min/kg and 11p, 21 ml/min/kg) and in dogs (11o, 12 ml/min/kg and 11p, 9 ml/min/kg).
Asunto(s)
Acetatos/síntesis química , Integrina alfa4beta1/antagonistas & inhibidores , Piperazinas/síntesis química , Piperidinas/síntesis química , Prolina/análogos & derivados , Acetatos/farmacocinética , Acetatos/farmacología , Animales , Perros , Espectroscopía de Resonancia Magnética , Masculino , Piperazinas/farmacocinética , Piperazinas/farmacología , Piperidinas/farmacocinética , Piperidinas/farmacología , Prolina/síntesis química , Prolina/farmacocinética , Prolina/farmacología , Ratas , Ratas Sprague-Dawley , Espectrometría de Masa Bombardeada por Átomos VelocesRESUMEN
An investigation into the structure-activity relationship of a lead compound, prolyl-5-aminopentanoic acid 4, led to the identification of a novel series of 4-piperidinylacetic acid, 1-piperazinylacetic acid, and 4-aminobenzoic acid derivatives as potent VLA-4 antagonists with low nanomolar IC(50) values. A representative compound morpholinyl-4-piperidinylacetic acid derivative (13d: IC(50)=4.4 nM) showed efficacy in the Ascaris-antigen sensitized murine airway inflammation model by oral administration.