RESUMEN
In a lead optimization effort towards NS5B NNI inhibitors, two multi-step parallel libraries were designed and successfully synthesized. Through this effort we discovered compound 9B, which achieved rigorous and delicate balance of inhibition across the common genotypes and mutants with <10 nM potency. In addition, the bicyclic compounds 9B exhibited improved FASSIF solubility over the tetracyclic compound MK-8876. This strategic approach demonstrated that, even within limited reaction scope, multi-step parallel libraries could provide access to more complex chemical space. This expedient access facilitates diverse, purpose-driven optimization of SAR and physicochemical properties.
Asunto(s)
Antivirales/farmacología , Benzofuranos/farmacología , Inhibidores Enzimáticos/farmacología , Proteínas no Estructurales Virales/antagonistas & inhibidores , Animales , Antivirales/síntesis química , Antivirales/farmacocinética , Benzofuranos/síntesis química , Benzofuranos/farmacocinética , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/farmacocinética , Hepacivirus/enzimología , Pruebas de Sensibilidad Microbiana , Estructura Molecular , Ratas Wistar , Bibliotecas de Moléculas Pequeñas/síntesis química , Bibliotecas de Moléculas Pequeñas/farmacocinética , Bibliotecas de Moléculas Pequeñas/farmacología , Relación Estructura-ActividadRESUMEN
Hepatitis C virus (HCV) NS5B polymerase is a prime target for the development of direct-acting antiviral drugs for the treatment of chronic HCV infection. Several novel and potent HCV NS5B non-nucleoside inhibitors with unique tetracyclic bezonfuran-based structures were prepared and evaluated. Similar to clinical developmental compound MK-8876, N-linked (compounds 1 and 2) and C-linked (compounds 3 and 4) tetracyclic structures maintained broad spectrum anti-replicon potency profiles and demonstrated moderate to excellent oral bioavailability and pharmacokinetic parameters across the three preclinical animal species. To better understand the importance of tetracyclic structures related to pan genotypic potency profiles especially against clinically relevant GT1a variants, the teracycles with different ring size were prepared and in vitro evaluations suggested compounds with six number ring have better overall potency profiles.
Asunto(s)
Antivirales/farmacología , Benzofuranos/farmacología , Diseño de Fármacos , Proteínas no Estructurales Virales/antagonistas & inhibidores , Antivirales/síntesis química , Antivirales/química , Benzofuranos/síntesis química , Benzofuranos/química , Relación Dosis-Respuesta a Droga , Pruebas de Sensibilidad Microbiana , Estructura Molecular , Relación Estructura-Actividad , Proteínas no Estructurales Virales/metabolismoRESUMEN
New synthetic methods were developed for the preparation of 2,3,6-trisubstituted 1-oxo-1,2-dihydroisoquinolines as CRTh2 antagonists. The isoquinolinone core could be constructed before the introduction of substitution groups or synthesized through a catalytic intramolecular cyclization reaction with desired substitution groups properly installed. These synthetic strategies have helped to accelerate the SAR development of this series, and potent lead compounds were identified in both the CRTh2 receptor binding assay and the CD11b biomarker assay.
Asunto(s)
Isoquinolinas/farmacología , Receptores Inmunológicos/antagonistas & inhibidores , Receptores de Prostaglandina/antagonistas & inhibidores , Relación Dosis-Respuesta a Droga , Humanos , Isoquinolinas/síntesis química , Isoquinolinas/química , Estructura Molecular , Relación Estructura-ActividadRESUMEN
A unified strategy was conceived and implemented to deliver conformationally constrained anilides based on their preferred cis-amide conformers. The imidazole/triazole mimicing amide bonds were designed, building upon an earlier discovery of a novel series of tricyclic lactams MK2 kinase inhibitors. This approach enabled rapid, modular synthesis of structurally novel analogs. The efficient SAR development led to the discovery of low molecular weight and potent MK2 non-ATP competitive inhibitors with good ligand efficiency, which led to improved permeability and oral exposure in rats.
Asunto(s)
Amidas/química , Azoles/farmacología , Descubrimiento de Drogas , Péptidos y Proteínas de Señalización Intracelular/antagonistas & inhibidores , Inhibidores de Proteínas Quinasas/farmacología , Proteínas Serina-Treonina Quinasas/antagonistas & inhibidores , Animales , Azoles/síntesis química , Azoles/química , Relación Dosis-Respuesta a Droga , Péptidos y Proteínas de Señalización Intracelular/metabolismo , Conformación Molecular , Permeabilidad/efectos de los fármacos , Inhibidores de Proteínas Quinasas/síntesis química , Inhibidores de Proteínas Quinasas/química , Proteínas Serina-Treonina Quinasas/metabolismo , Ratas , Relación Estructura-ActividadRESUMEN
Isoxazoles are frequently used amide isosteres, as shown in the context of discovery of CRTh2 antagonists from amide 1 to isoxazole 2. However, persistent agonism and poor solubility in isoxazole series presented challenges to its further development. Based on the concept of quality by design (QbD), 5,5-disubstituted isoxazolines 3 were introduced. The chirality at 5 position of isoxazolines controlled the switch between two modes of actions, which led to a novel series of pure antagonists. This non-planar motif also conferred a change of shape of these molecules, which avoided flat structures and improved their physical properties.
Asunto(s)
Amidas/química , Diseño de Fármacos , Isoxazoles/química , Quinazolinonas/química , Receptores Inmunológicos/antagonistas & inhibidores , Receptores de Prostaglandina/antagonistas & inhibidores , Animales , Perros , Semivida , Haplorrinos , Humanos , Isoxazoles/síntesis química , Isoxazoles/farmacocinética , Quinazolinonas/síntesis química , Quinazolinonas/farmacocinética , Ratas , Ratas Wistar , Receptores Inmunológicos/metabolismo , Receptores de Prostaglandina/metabolismo , Solubilidad , Relación Estructura-ActividadRESUMEN
Oncogenic mutations in the RAS gene account for 30% of all human tumors; more than 60% of which present as KRAS mutations at the hotspot codon 12. After decades of intense pursuit, a covalent inhibition strategy has enabled selective targeting of this previously "undruggable" target. Herein, we disclose our journey toward the discovery of MK-1084, an orally bioavailable and low-dose KRASG12C covalent inhibitor currently in phase I clinical trials (NCT05067283). We leveraged structure-based drug design to identify a macrocyclic core structure, and hypothesis-driven optimization of biopharmaceutical properties to further improve metabolic stability and tolerability.
Asunto(s)
Descubrimiento de Drogas , Proteínas Proto-Oncogénicas p21(ras) , Animales , Perros , Humanos , Ratones , Ratas , Administración Oral , Antineoplásicos/farmacología , Antineoplásicos/farmacocinética , Antineoplásicos/química , Disponibilidad Biológica , Relación Dosis-Respuesta a Droga , Proteínas Proto-Oncogénicas p21(ras)/antagonistas & inhibidores , Proteínas Proto-Oncogénicas p21(ras)/genética , Proteínas Proto-Oncogénicas p21(ras)/metabolismo , Relación Estructura-ActividadRESUMEN
General methods for the highly site-selective Suzuki monocoupling of 3,5-dichloropyridazines have been discovered. By changing the ligand employed, the preferred coupling site can be switched from the 3-position to the 5-position, typically considered the less reactive C-X bond. These conditions are applicable to the coupling of a wide variety of aryl-, heteroaryl-, and vinylboronic acids with high selectivities, thus enabling the rapid construction of diverse arrays of diarylpyradazines in a modular fashion.
Asunto(s)
Piridinas/síntesis química , Ligandos , Estructura Molecular , Piridinas/químicaRESUMEN
Conformation restriction of linear N-alkylanilide MK2 inhibitors to their E-conformer was developed. This strategy enabled rapid advance in identifying a series of potent non-ATP competitive inhibitors that exhibited cell based activity in anti-TNFα assay.
Asunto(s)
Anilidas/química , Péptidos y Proteínas de Señalización Intracelular/antagonistas & inhibidores , Lactamas/química , Inhibidores de Proteínas Quinasas/química , Proteínas Serina-Treonina Quinasas/antagonistas & inhibidores , Adenosina Trifosfato/química , Adenosina Trifosfato/metabolismo , Anilidas/síntesis química , Anilidas/metabolismo , Unión Competitiva , Evaluación Preclínica de Medicamentos , Humanos , Péptidos y Proteínas de Señalización Intracelular/metabolismo , Lactamas/síntesis química , Lactamas/metabolismo , Unión Proteica , Inhibidores de Proteínas Quinasas/síntesis química , Inhibidores de Proteínas Quinasas/metabolismo , Proteínas Serina-Treonina Quinasas/metabolismo , Estereoisomerismo , Relación Estructura-ActividadRESUMEN
In an attempt to further improve overall profiles of the oxadiazine series of GSMs, in particular the hERG activity, conformational modifications of the core structure resulted in the identification of fused oxadiazepines such as 7i which had an improved hERG inhibition profile and was a highly efficacious GSM in vitro and in vivo in rats. These SAR explorations offer opportunities to identify potential drugs to treat Alzheimer's disease.
Asunto(s)
Enfermedad de Alzheimer/tratamiento farmacológico , Secretasas de la Proteína Precursora del Amiloide/metabolismo , Azepinas/síntesis química , Descubrimiento de Drogas , Canales de Potasio Éter-A-Go-Go/antagonistas & inhibidores , Animales , Azepinas/química , Azepinas/farmacología , Canal de Potasio ERG1 , Activación Enzimática/efectos de los fármacos , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/farmacología , Humanos , Concentración 50 Inhibidora , Estructura Molecular , Ratas , Relación Estructura-ActividadRESUMEN
Facile synthesis of two new series of tetracyclic azepine and oxazocine analogs is described. These analogs were evaluated for their potential as MAPKAP-K2 (MK2) inhibitors and several were found to be potent at inhibiting MK2 with a non-ATP competitive binding mode.
Asunto(s)
Azepinas/farmacología , Péptidos y Proteínas de Señalización Intracelular/antagonistas & inhibidores , Oxazocinas/farmacología , Inhibidores de Proteínas Quinasas/farmacología , Proteínas Serina-Treonina Quinasas/antagonistas & inhibidores , Azepinas/síntesis química , Azepinas/química , Humanos , Estructura Molecular , Oxazocinas/síntesis química , Oxazocinas/química , Inhibidores de Proteínas Quinasas/síntesis química , Inhibidores de Proteínas Quinasas/química , Estereoisomerismo , Relación Estructura-ActividadRESUMEN
The synthesis and SAR of a novel series of 4-azabenzoxazole histamine H(3) antagonists is described. Introduction of substituted phenyl, pyridyl and fused heterocyclic groups to the 6-position of the 4-azabenzoxazole core gave a series of compounds with good H(3) antagonist activity in both ex vivo and in vivo assays.
Asunto(s)
Benzoxazoles/química , Benzoxazoles/farmacología , Antagonistas de los Receptores Histamínicos H3/química , Antagonistas de los Receptores Histamínicos H3/farmacología , Receptores Histamínicos H3/metabolismo , Animales , Compuestos Aza/síntesis química , Compuestos Aza/química , Compuestos Aza/farmacocinética , Compuestos Aza/farmacología , Benzoxazoles/síntesis química , Benzoxazoles/farmacocinética , Antagonistas de los Receptores Histamínicos H3/síntesis química , Antagonistas de los Receptores Histamínicos H3/farmacocinética , Humanos , Ratones , Ratas , Relación Estructura-ActividadRESUMEN
A three-step protocol for SAR development was introduced and applied to the SAR studies of the MK2 inhibitor program. Following this protocol, key conformational features and functional groups for improving MK2 inhibitor activity were quickly identified. Through this effort, the initial gap observed between in vitro binding activity and cellular activity in the lead identification stage was very much reduced. Compound 28 was identified with single digit binding activity (IC(50)=8 nM) and good cellular activity (EC(50)=310 nM). This provides further evidence that non-ATP-competitive binding MK2 inhibitors are feasible by targeting the outside ATP pocket.
Asunto(s)
Química Farmacéutica/métodos , Péptidos y Proteínas de Señalización Intracelular/antagonistas & inhibidores , Inhibidores de Proteínas Quinasas/síntesis química , Inhibidores de Proteínas Quinasas/farmacología , Proteínas Serina-Treonina Quinasas/antagonistas & inhibidores , Adenosina Trifosfato/química , Animales , Diseño de Fármacos , Humanos , Concentración 50 Inhibidora , Ratones , Modelos Químicos , Conformación Molecular , Unión Proteica , Relación Estructura-ActividadRESUMEN
A structure-activity relationship study was undertaken to address the lack of oral exposure of the H3 antagonist 1, which incorporated an arylketone. Among a number of sub-series, the 4H-pyrido[1,2-a]pyrimidin-4-one analog 21 showed an improved PK profile in rat and mouse and was active in an obesity model. The pyrimidin-4-one proved to be a novel and useful ketone bioisostere.
Asunto(s)
Antagonistas de los Receptores Histamínicos H3/farmacocinética , Tiadiazoles/farmacología , Administración Oral , Animales , Cetonas , Obesidad/tratamiento farmacológico , Ratas , Relación Estructura-Actividad , Tiadiazoles/farmacocinéticaRESUMEN
Based on in house screening lead compound 1 for the NAR project, SAR studies have been focused on the modification of the C2 ethers of the pyrimidinedione core structure. In this effort, an unpredictable SAR trend was overcome in the alkyl ether and arylalkyl ether series to identify compound 24 with improved in vitro activity compared to nicotinic acid. More consistent and predictable SAR was achieved in the propargyl ether series. Lead compound 41 was identified with good in vitro and in vivo activity in rat, and much improved rat PK profile.
Asunto(s)
Éteres/farmacología , Lactonas/farmacología , Pirimidinas/farmacología , Receptores Nicotínicos/metabolismo , Éteres/síntesis química , Éteres/química , Humanos , Lactonas/síntesis química , Lactonas/química , Estructura Molecular , Pirimidinas/síntesis química , Pirimidinas/química , Relación Estructura-ActividadRESUMEN
The combination of insulin and incretin-based therapies has emerged as a potential promising tactic for the treatment of diabetes. Here we report the first example of a unimolecular triagonist to simultaneously target insulin, GLP-1, and glucagon receptors, aiming for better glycemic control and superior weight loss. The strategy for constructing such a unimolecular triagonist is the conjugation of the insulin moiety and GLP-1R/GCGR coagonist peptide via alkyne-azide click chemistry. Two tractable series differentiated by insulin conjugation sites, B1F and B29K, were identified. Triagonist 13 prepared through the conjugation at insulin B1F and position 24 of GLP-1R/GCGR coagonist exhibited insulin activity comparable to that of insulin degludec and potent and balanced GLP-1R and GCGR activities. Pharmacokinetic profiles of 13 in both rat and minipig were also discussed.
RESUMEN
Peptide-based analogues of the gut-derived incretin hormone, glucagon-like peptide 1 (GLP1), stimulate insulin secretion in a glucose-dependent manner. Currently marketed GLP1 receptor (GLP1R) agonists are safe and effective in the management of Type 2 diabetes but often offer only modest weight loss. This has prompted the search for safe and effective alternatives to enhance the weight loss component of these treatments. We have demonstrated that concomitant activation GLP1R and the glucagon receptor (GCGR) can improve glucose metabolism and provide superior weight loss when compared to selective GLP1R agonism in preclinical species. This paper will highlight chemistry structure-activity relationship optimization and summarize in vivo efficacy studies toward the discovery of a once daily balanced dual agonist 12 (MK-1462), which was advanced into clinical trials.
RESUMEN
Inhibitor cystine knot peptides, derived from venom, have evolved to block ion channel function but are often toxic when dosed at pharmacologically relevant levels in vivo. The article describes the design of analogues of ProTx-II that safely display systemic in vivo blocking of Nav1.7, resulting in a latency of response to thermal stimuli in rodents. The new designs achieve a better in vivo profile by improving ion channel selectivity and limiting the ability of the peptides to cause mast cell degranulation. The design rationale, structural modeling, in vitro profiles, and rat tail flick outcomes are disclosed and discussed.
Asunto(s)
Canal de Sodio Activado por Voltaje NAV1.7/efectos de los fármacos , Dolor/tratamiento farmacológico , Bloqueadores de los Canales de Sodio/síntesis química , Bloqueadores de los Canales de Sodio/farmacología , Venenos de Araña/síntesis química , Animales , Degranulación de la Célula/efectos de los fármacos , Cistina/química , Diseño de Fármacos , Calor , Mastocitos/efectos de los fármacos , Modelos Moleculares , Dimensión del Dolor/efectos de los fármacos , Ratas , Venenos de Araña/farmacologíaRESUMEN
We herein report the discovery of four series of fused 5,6-bicyclic heterocycles as γ-secretase modulators. Synthesis and SAR of these series are discussed. These compounds represent a new class of γ-secretase modulators that demonstrate moderate to good in vitro potency in inhibiting Aß(42) production.
Asunto(s)
Secretasas de la Proteína Precursora del Amiloide/metabolismo , Péptidos beta-Amiloides/antagonistas & inhibidores , Compuestos Bicíclicos Heterocíclicos con Puentes/química , Compuestos Bicíclicos Heterocíclicos con Puentes/farmacología , Enfermedad de Alzheimer/tratamiento farmacológico , Péptidos beta-Amiloides/metabolismo , Animales , Compuestos Bicíclicos Heterocíclicos con Puentes/farmacocinética , Humanos , Ratas , Relación Estructura-ActividadRESUMEN
A series of 2-piperidinopiperidine-5-arylthiadiazoles was synthesized and subjected to a structure-activity relationship (SAR) investigation. The potency of this series was improved to the single digit nanomolar range. The key analogs were shown to be free of P450 issues, and they also maintained good ex vivo activity and brain penetration.
Asunto(s)
Antagonistas de los Receptores Histamínicos/química , Antagonistas de los Receptores Histamínicos/farmacología , Receptores Histamínicos H3/metabolismo , Tiadiazoles/química , Tiadiazoles/farmacología , Animales , Encéfalo/metabolismo , Antagonistas de los Receptores Histamínicos/farmacocinética , Humanos , Ratones , Ratas , Relación Estructura-Actividad , Tiadiazoles/farmacocinéticaRESUMEN
Recent data suggest that the inhibition of arginase (ARG) has therapeutic potential for the treatment of a number of indications ranging from pulmonary and vascular disease to cancer. Thus, high demand exists for selective small molecule ARG inhibitors with favorable druglike properties and good oral bioavailability. In light of the significant challenges associated with the unique physicochemical properties of previously disclosed ARG inhibitors, we use structure-based drug design combined with a focused optimization strategy to discover a class of boronic acids featuring a privileged proline scaffold with superior potency and oral bioavailability. These compounds, exemplified by inhibitors 4a, 18, and 27, demonstrated a favorable overall profile, and 4a was well tolerated following multiple days of dosing at concentrations that exceed those required for serum arginase inhibition and concomitant arginine elevation in a syngeneic mouse carcinoma model.