RESUMEN
Structure-based drug design is an iterative process that is an established means to accelerate lead optimization, and is most powerful when integrated with information from different sources. Herein is described the use of such methods in conjunction with deconstruction and re-optimization of a diverse series of ASK1 chemotypes along with high-throughput screening that lead to the identification of a novel series of efficient ASK1 inhibitors displaying robust MAP3K pathway inhibition.
Asunto(s)
Diseño de Fármacos , MAP Quinasa Quinasa Quinasa 5/antagonistas & inhibidores , Inhibidores de Proteínas Quinasas/química , Inhibidores de Proteínas Quinasas/farmacología , Evaluación Preclínica de Medicamentos , Ensayos Analíticos de Alto Rendimiento , Humanos , MAP Quinasa Quinasa Quinasa 5/química , MAP Quinasa Quinasa Quinasa 5/metabolismo , Sistema de Señalización de MAP Quinasas/efectos de los fármacos , Simulación del Acoplamiento MolecularRESUMEN
In 2022, 23 new small molecule chemical entities were approved as drugs by the United States FDA, European Union EMA, Japan PMDA, and China NMPA. This review describes the synthetic approach demonstrated on largest scale for each new drug based on patent or primary literature. The synthetic routes highlight practical methods to construct molecules, sometimes on the manufacturing scale, to access the new drugs. Ten additional drugs approved in 2021 and one approved in 2020 are included that were not covered in the previous year's review.
Asunto(s)
Aprobación de Drogas , Estados Unidos , Japón , United States Food and Drug Administration , ChinaRESUMEN
Selective inhibition of the RGD (Arg-Gly-Asp) integrin αvß1 has been recently identified as an attractive therapeutic approach for the treatment of liver fibrosis given its function, target expression, and safety profile. Our identification of a non-RGD small molecule lead followed by focused, systematic changes to the core structure utilizing a crystal structure, in silico modeling, and a tractable synthetic approach resulted in the identification of a potent small molecule exhibiting a remarkable affinity for αvß1 relative to several other integrin isoforms measured. Azabenzimidazolone 25 demonstrated antifibrotic efficacy in an in vivo rat liver fibrosis model and represents a tool compound capable of further exploring the biological consequences of selective αvß1 inhibition.
Asunto(s)
Diseño de Fármacos , Receptores de Vitronectina , Animales , Ratas , Humanos , Receptores de Vitronectina/antagonistas & inhibidores , Receptores de Vitronectina/metabolismo , Relación Estructura-Actividad , Cirrosis Hepática/tratamiento farmacológico , Modelos Moleculares , Descubrimiento de Drogas , Ratas Sprague-Dawley , Masculino , Cristalografía por Rayos X , Bencimidazoles/farmacología , Bencimidazoles/química , Bencimidazoles/síntesis químicaRESUMEN
Each year, new drugs are introduced to the market, representing structures that have affinity for biological targets implicated in human diseases and conditions. These new chemical entities (NCEs), particularly small molecules and antibody-drug conjugates, provide insight into molecular recognition and serve as potential leads for the design of future medicines. This annual review is part of a continuing series highlighting the most likely process-scale synthetic approaches to 35 NCEs that were first approved anywhere in the world during 2021.
Asunto(s)
Diseño de Fármacos , Humanos , Preparaciones Farmacéuticas , Inmunoconjugados/químicaRESUMEN
New drugs introduced to the market are privileged structures that have affinities for biological targets implicated in human diseases and conditions. These new chemical entities (NCEs), particularly small molecules and antibody-drug conjugates (ADCs), provide insight into molecular recognition and simultaneously function as leads for the design of future medicines. This Review is part of a continuing series presenting the most likely process-scale synthetic approaches to 44 new chemical entities approved for the first time anywhere in the world during 2020.
Asunto(s)
Diseño de Fármacos , Inmunoconjugados , HumanosRESUMEN
New drugs introduced to the market are privileged structures having affinities for biological targets implicated in human diseases and conditions. These new chemical entities (NCEs), particularly small molecules and antibody-drug conjugates, provide insight into molecular recognition and simultaneously function as leads for the design of future medicines. This review is part of a continuing series presenting the most likely process-scale synthetic approaches to 40 NCEs approved for the first time anywhere in the world in 2019.
Asunto(s)
Técnicas de Química Sintética/métodos , Compuestos Orgánicos/síntesis química , Preparaciones Farmacéuticas/síntesis química , Animales , HumanosRESUMEN
BACKGROUND: 5-HT4 receptor (5-HT4 R) agonists exert prokinetic actions in the GI tract, but non-selective actions and potential for stimulation of non-target 5-HT4 Rs have limited their use. Since 5-HT4 Rs are expressed in the colonic epithelium and their stimulation accelerates colonic propulsion in vitro, we tested whether luminally acting 5-HT4 R agonists promote intestinal motility. METHODS: Non-absorbed 5-HT4 R agonists, based on prucalopride and naronapride, were assessed for potency at the 5-HT4 R in vitro, and for tissue and serum distribution in vivo in mice. In vivo assessment of prokinetic potential included whole gut transit, colonic motility, fecal output, and fecal water content. Colonic motility was also studied ex vivo in mice treated in vivo. Immunofluorescence was used to evaluate receptor distribution in human intestinal mucosa. KEY RESULTS: Pharmacological screening demonstrated selectivity and potency of test agonists for 5-HT4 R. Bioavailability studies showed negligible serum detection. Gavage of agonists caused faster whole gut transit and colonic motility, increased fecal output, and elevated fecal water content. Prokinetic actions were blocked by a 5-HT4 R antagonist and were not detected in 5-HT4 R knockout mice. Agonist administration promoted motility in models of constipation. Evaluation of motility patterns ex vivo revealed enhanced contractility in the middle and distal colon. Immunoreactivity for 5-HT4 R is present in the epithelial layer of the human small and large intestines. CONCLUSIONS AND INFERENCES: These findings demonstrated that stimulation of epithelial 5-HT4 Rs can potentiate propulsive motility and support the concept that mucosal 5-HT4 Rs could represent a safe and effective therapeutic target for the treatment of constipation.
Asunto(s)
Colon/fisiología , Motilidad Gastrointestinal/fisiología , Mucosa Intestinal/fisiología , Receptores de Serotonina 5-HT4/fisiología , Agonistas del Receptor de Serotonina 5-HT4/farmacología , Animales , Células CHO , Colon/efectos de los fármacos , Estreñimiento/tratamiento farmacológico , Estreñimiento/fisiopatología , Cricetinae , Cricetulus , Motilidad Gastrointestinal/efectos de los fármacos , Humanos , Mucosa Intestinal/efectos de los fármacos , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Ratones Transgénicos , Agonistas del Receptor de Serotonina 5-HT4/uso terapéuticoRESUMEN
[This corrects the article DOI: 10.1021/acsmedchemlett.6b00481.].
RESUMEN
Apoptosis signal-regulating kinase 1 (ASK1/MAP3K) is a mitogen-activated protein kinase family member shown to contribute to acute ischemia/reperfusion injury. Using structure-based drug design, deconstruction, and reoptimization of a known ASK1 inhibitor, a lead compound was identified. This compound displayed robust MAP3K pathway inhibition and reduction of infarct size in an isolated perfused heart model of cardiac injury.
RESUMEN
AMP-activated protein kinase (AMPK) plays an essential role as a cellular energy sensor and master regulator of metabolism in eukaryotes. Dysregulated lipid and carbohydrate metabolism resulting from insulin resistance leads to hyperglycemia, the hallmark of type 2 diabetes mellitus (T2DM). While pharmacological activation of AMPK is anticipated to improve these parameters, the discovery of selective, direct activators has proven challenging. We now describe a hit-to-lead effort resulting in the discovery of a potent and selective class of benzimidazole-based direct AMPK activators, exemplified by 5-((5-([1,1'-biphenyl]-4-yl)-6-chloro-1H-benzo[d]imidazol-2-yl)oxy)-2-methylbenzoic acid, 42 (MK-3903). Compound 42 exhibited robust target engagement in mouse liver following oral dosing, leading to improved lipid metabolism and insulin sensitization in mice.
Asunto(s)
Proteínas Quinasas Activadas por AMP/metabolismo , Bencimidazoles/farmacología , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Administración Oral , Animales , Bencimidazoles/administración & dosificación , Bencimidazoles/uso terapéutico , Descubrimiento de Drogas , Resistencia a la Insulina , Metabolismo de los Lípidos/efectos de los fármacos , RatonesRESUMEN
The catalytic aerobic oxidation of benzylic alcohols to corresponding aldehydes has been investigated employing a tetradentate copper(ii) complex that incorporates N-methyl imidazole (NMI) as an integral part of an N4-ligand framework. The complex [L3-Cu]2+ [(L3 = 1-methyl-4,5-dihydro-1H-imidazol-2-yl)methyl(2-ethyl)amine] has been synthesized, characterized by spectroscopic and structural techniques, and its catalytic activity towards the aerobic oxidation of benzylic alcohols studied under ambient conditions. Catalytic turnover required addition of the nitroxyl radical initiator TEMPO. No oxidation was observed with hydroxyl radical initiators H2O2 or tetrabutylammonium hydroperoxide. Additional NMI enhanced turnover with yields up to 99% within 4 hours. The relative quantities of substrate, catalyst, TEMPO, and NMI were systematically varied in a series of experiments to determine optimal conditions. The effect of oxygen at various flow rates as an alternate to ambient aerobic conditions was also investigated.
Asunto(s)
Glaucoma/terapia , Optometría , Rol Profesional , Adulto , Anciano , Humanos , Persona de Mediana EdadRESUMEN
Oral delivery of previously disclosed purine and benzimidazole fructose-1,6-bisphosphatase (FBPase) inhibitors via prodrugs failed, which was likely due to their high molecular weight (>600). Therefore, a smaller scaffold was desired, and a series of phosphonic acid-containing thiazoles, which exhibited high potency against human liver FBPase (IC(50) of 10-30 nM) and high selectivity relative to other 5'-adenosinemonophosphate (AMP)-binding enzymes, were discovered using a structure-guided drug design approach. The initial lead compound (30j) produced profound glucose lowering in rodent models of type 2 diabetes mellitus (T2DM) after parenteral administration. Various phosphonate prodrugs were explored without success, until a novel phosphonic diamide prodrug approach was implemented, which delivered compound 30j with good oral bioavailability (OBAV) (22-47%). Extensive lead optimization of both the thiazole FBPase inhibitors and their prodrugs culminated in the discovery of compound 35n (MB06322) as the first oral FBPase inhibitor advancing to human clinical trials as a potential treatment for T2DM.
Asunto(s)
Alanina/análogos & derivados , Amidas/síntesis química , Diabetes Mellitus Experimental/tratamiento farmacológico , Fructosa-Bifosfatasa/antagonistas & inhibidores , Hipoglucemiantes/síntesis química , Organofosfonatos/síntesis química , Profármacos/síntesis química , Tiazoles/síntesis química , Administración Oral , Alanina/síntesis química , Alanina/farmacocinética , Alanina/farmacología , Amidas/farmacocinética , Amidas/farmacología , Animales , Disponibilidad Biológica , Proteínas Sanguíneas/metabolismo , Diabetes Mellitus Experimental/sangre , Diabetes Mellitus Tipo 2/sangre , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Humanos , Hipoglucemiantes/farmacocinética , Hipoglucemiantes/farmacología , Masculino , Ratones , Organofosfonatos/farmacocinética , Organofosfonatos/farmacología , Profármacos/farmacocinética , Profármacos/farmacología , Unión Proteica , Ratas , Ratas Sprague-Dawley , Relación Estructura-Actividad , Tiazoles/farmacocinética , Tiazoles/farmacologíaRESUMEN
Efforts to enhance the inhibitory potency of the initial purine series of fructose-1,6-bisphosphatase (FBPase) inhibitors led to the discovery of a series of benzimidazole analogues with human FBPase IC(50)s < 100 nM. Inhibitor 4.4 emerged as a lead compound based on its potent inhibition of human liver FBPase (IC(50) = 55 nM) and significant glucose lowering in normal fasted rats. Intravenous administration of 4.4 to Zucker diabetic fatty rats led to rapid and robust glucose lowering, thereby providing the first evidence that FBPase inhibitors could improve glycemia in animal models of type 2 diabetes.
Asunto(s)
Adenosina Monofosfato/química , Bencimidazoles/farmacología , Diseño de Fármacos , Inhibidores Enzimáticos/farmacología , Fructosa-Bifosfatasa/antagonistas & inhibidores , Organofosfonatos/química , Adenosina Monofosfato/metabolismo , Animales , Bencimidazoles/síntesis química , Bencimidazoles/química , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Modelos Animales de Enfermedad , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/química , Humanos , Hígado/enzimología , Estructura Molecular , Ratas , Ratas Zucker , Estereoisomerismo , Relación Estructura-ActividadRESUMEN
Evolution of P(1)-argininal inhibitor prototypes led to a series of non-covalent P(3)-7-membered lactam inhibitors 1a-w, featuring novel peptidomimetic units that probe each of the S(1), S(2), and S(3) specificity pockets of thrombin. Rigid P(1)-arginine surrogates possessing a wide range of basicity (calcd pK(a)'s approximately neutral-14) were surveyed. The design, synthesis, and biological activity of these targets are presented.
Asunto(s)
Antitrombinas/síntesis química , Lactamas/síntesis química , Animales , Antitrombinas/farmacocinética , Antitrombinas/farmacología , Disponibilidad Biológica , Coagulación Sanguínea/efectos de los fármacos , Perros , Lactamas/farmacocinética , Lactamas/farmacología , Estructura Molecular , Serina Endopeptidasas/metabolismo , Relación Estructura-Actividad , Tripsina/farmacologíaRESUMEN
Investigations on P(2)-P(3)-heterocyclic dipeptide surrogates directed towards identification of an orally bioavailable thrombin inhibitor led us to pursue novel classes of achiral, non-covalent P(1)-arginine derivatives. The design, synthesis, and biological activity of inhibitors NC1-NC30 that feature three classes of monocyclic P(1)-arginine surrogates will be disclosed: (1) (hetero)aromatic amidines, amines and hydroxyamidines, (2) 2-aminopyrazines, and (3) 2-aminopyrimidines and 2-aminotetrahydropyrimidines.
Asunto(s)
Antitrombinas/química , Antitrombinas/farmacología , Arginina/química , Compuestos Heterocíclicos/química , Animales , Antitrombinas/síntesis química , Perros , Relación Estructura-ActividadRESUMEN
Novel, potent, and highly selective classes of thrombin inhibitors were identified, which resulted from judicious combination of P4-aromatics and P2-P3-heterocyclic dipeptide surrogates with weakly basic (calcd pKa approximately non-basic-8.6) bicyclic P1-arginine mimics. The design, synthesis, and biological activity of achiral, non-covalent, orally bioavailable inhibitors NC1-NC44 featuring P1-indazoles, benzimidazoles, indoles, benzotriazoles, and aminobenzisoxazoles is disclosed.