RESUMEN
A property-focused optimization strategy was employed to modify the carboxylic acid head group of a class of EP4 agonists in order to minimize its absorption upon oral administration. The resulting oxalic acid monohydrazide-derived carboxylate isostere demonstrated utility as a class of prodrug showing colon-targeted delivery of parent agonist 2, with minimal exposure observed in the plasma. Oral administration of NXT-10796 demonstrated tissue specific activation of the EP4 receptor through modulation of immune genes in the colon, without modulation of EP4 driven biomarkers in the plasma compartment. Although further in depth understanding of the conversion of NXT-10796 is required for further assessment of the developability of this series of prodrugs, using NXT-10796 as a tool molecule has allowed us to confirm that tissue-specific modulation of an EP4-modulated gene signature is possible, which allows for further evaluation of this therapeutic modality in rodent models of human disease.
Asunto(s)
Enfermedades Inflamatorias del Intestino , Profármacos , Humanos , Profármacos/farmacología , Profármacos/uso terapéutico , Enfermedades Inflamatorias del Intestino/tratamiento farmacológico , Colon , Subtipo EP4 de Receptores de Prostaglandina E/agonistasRESUMEN
Novel prostaglandin E2 receptor 4 (EP4) agonists featuring a pyridone core and an allylic alcohol ω-chain were discovered. These agonists were shown to be selective over EP1, EP2 and EP3. Analogs harboring a 4-carboxylic acid phenethyl α-chain displayed improved potency over those containing an n-heptanoic acid chain. Key SAR relationships were also identified.
Asunto(s)
Propanoles/química , Piridonas/química , Subtipo EP4 de Receptores de Prostaglandina E/agonistas , Humanos , Propanoles/metabolismo , Isoformas de Proteínas/agonistas , Isoformas de Proteínas/metabolismo , Piridonas/metabolismo , Subtipo EP4 de Receptores de Prostaglandina E/metabolismo , Relación Estructura-ActividadRESUMEN
A series of TRPA1 antagonists is described having a 4-aryloxy-1H-pyrrolo[3,2-c]pyridine or a 1-aryloxyisoquinoline scaffold. These compounds have high ligand efficiency and favorable physical properties and may thus serve as scaffolds for further optimization.
Asunto(s)
Descubrimiento de Drogas , Isoquinolinas/farmacología , Proteínas del Tejido Nervioso/antagonistas & inhibidores , Piridinas/farmacología , Pirroles/farmacología , Canales de Potencial de Receptor Transitorio/antagonistas & inhibidores , Canales de Calcio , Relación Dosis-Respuesta a Droga , Humanos , Isoquinolinas/síntesis química , Isoquinolinas/química , Estructura Molecular , Piridinas/síntesis química , Piridinas/química , Pirroles/síntesis química , Pirroles/química , Relación Estructura-Actividad , Canal Catiónico TRPA1RESUMEN
The optimization of a novel series of non-nucleoside reverse transcriptase inhibitors (NNRTI) led to the identification of pyridone 36. In cell cultures, this new NNRTI shows a superior potency profile against a range of wild type and clinically relevant, resistant mutant HIV viruses. The overall favorable preclinical pharmacokinetic profile of 36 led to the prediction of a once daily low dose regimen in human. NNRTI 36, now known as MK-1439, is currently in clinical development for the treatment of HIV infection.
Asunto(s)
Fármacos Anti-VIH/farmacología , Descubrimiento de Drogas , Farmacorresistencia Viral/efectos de los fármacos , VIH-1/efectos de los fármacos , Piridonas/química , Piridonas/farmacología , Inhibidores de la Transcriptasa Inversa/síntesis química , Inhibidores de la Transcriptasa Inversa/farmacología , Triazoles/química , Triazoles/farmacología , Animales , Fármacos Anti-VIH/síntesis química , Fármacos Anti-VIH/química , Células Cultivadas , Cristalografía por Rayos X , Perros , VIH-1/genética , Humanos , Concentración 50 Inhibidora , Estructura Molecular , Mutación , Ratas , Ratas Sprague-Dawley , Inhibidores de la Transcriptasa Inversa/químicaRESUMEN
ATR is a key kinase in the DNA-damage response (DDR) that is synthetic lethal with several other DDR proteins, making it an attractive target for the treatment of genetically selected solid tumors. Herein we describe the discovery of a novel ATR inhibitor guided by a pharmacophore model to position a key hydrogen bond. Optimization was driven by potency and selectivity over the related kinase mTOR, resulting in the identification of camonsertib (RP-3500) with high potency and excellent ADME properties. Preclinical evaluation focused on the impact of camonsertib on myelosuppression, and an exploration of intermittent dosing schedules to allow recovery of the erythroid compartment and mitigate anemia. Camonsertib is currently undergoing clinical evaluation both as a single agent and in combination with talazoparib, olaparib, niraparib, lunresertib, or gemcitabine (NCT04497116, NCT04972110, NCT04855656). A preliminary recommended phase 2 dose for monotherapy was identified as 160 mg QD given 3 days/week.
Asunto(s)
Neoplasias , Humanos , Proteínas de la Ataxia Telangiectasia Mutada , Neoplasias/tratamiento farmacológico , Inhibidores de Proteínas Quinasas/farmacología , Inhibidores de Proteínas Quinasas/uso terapéutico , GemcitabinaRESUMEN
DNA polymerase theta (Polθ) is an attractive synthetic lethal target for drug discovery, predicted to be efficacious against breast and ovarian cancers harboring BRCA-mutant alleles. Here, we describe our hit-to-lead efforts in search of a selective inhibitor of human Polθ (encoded by POLQ). A high-throughput screening campaign of 350,000 compounds identified an 11 micromolar hit, giving rise to the N2-substituted fused pyrazolo series, which was validated by biophysical methods. Structure-based drug design efforts along with optimization of cellular potency and ADME ultimately led to the identification of RP-6685: a potent, selective, and orally bioavailable Polθ inhibitor that showed in vivo efficacy in an HCT116 BRCA2-/- mouse tumor xenograft model.
Asunto(s)
ADN Polimerasa Dirigida por ADN , Neoplasias Ováricas , Animales , Replicación del ADN , ADN Polimerasa Dirigida por ADN/metabolismo , Diseño de Fármacos , Descubrimiento de Drogas , Femenino , Humanos , RatonesRESUMEN
A new concerted silver ion-mediated Grob fragmentation process is described in which a 1,2-dihydropyridinium ion is formed and trapped in situ with Grignard reagents in a highly regio- and diastereoselective fashion. Using this methodology, 2,3,6-trisubstituted piperidines were synthesized in good yields and further derivatized to polysubstituted indolizidine.
Asunto(s)
Yoduros/química , Piperidinas/química , Piperidinas/síntesis química , Plata/química , Estereoisomerismo , Especificidad por SustratoRESUMEN
Aryl-substituted five-membered heteroaromatics have attracted great interest over the past years due to their presence in a large number of pharmaceuticals and natural products. Recently, an advance in the preparation of these scaffolds was achieved by employing a C-H functionalization strategy. This method allows easy access to these biaryl motifs by precluding the necessity of preparing specific coupling partners, although poor regioselectivity is sometimes observed when more than one reactive C-H is present on the substrate. In an effort to circumvent this liability, we envisioned the use of a carboxylic acid moiety as a blocking group that could be later functionalized or removed. Remarkably, the coupling was found to occur exclusively at the position previously occupied by the acid, even in the presence of a reactive C-H group. This selective transformation was also found to proceed with other heteroaromatic carboxylic acids, allowing for the preparation of a variety of aryl-substituted heteroaromatics that would be difficult to obtain via other methods.
RESUMEN
[reaction: see text] Chiral diols are important molecules with widespread use as chiral auxiliaries and ligands in enantioselective synthesis. Therefore, efficient and practical syntheses of highly dissymmetrical nonracemic diols are still a meaningful pursuit. Two new routes to access camphor-derived chiral diol 1 have been developed. One route employs camphorquinone (3) as the starting material, affording in only two steps the desired diol in 55% overall yield. The second route, from camphor (2), leads to the desired diol in an efficient four-step synthesis, with an overall yield of 55%.