RESUMEN
The status of industrial Medicinal Chemistry was discussed with European Medicinal Chemistry Leaders from large to mid-sized pharma and CRO companies as well as biotechs. The chemical modality space has expanded recently from small molecules to address new challenging targets. Besides the classical SAR/SPR optimization of drug molecules also their 'greenness' has increasing importance. The entire pharma discovery ecosystem has developed significantly. Beyond pharma and academia new key players such as Biotech and integrated CROs as well as Digital companies have appeared and are now to a large extend fueled by VC money. Digitalization is happening everywhere but surprisingly did not change speed and success rates of projects so far. Future Medicinal Chemists will still have to be excellent synthetic chemists but in addition they must be knowledgeable in new computational areas such as data sciences. Their ability to collaborate and to work in teams is key.
Asunto(s)
Química Farmacéutica , Industria Farmacéutica , Ecosistema , Europa (Continente)RESUMEN
Calcitonin gene-related peptide (CGRP) has been implicated in acute migraine pathogenesis. In an effort to identify novel CGRP receptor antagonists for the treatment of migraine, we have discovered thiazolidinone 49, a potent (Ki=30 pM, IC50=1 nM), orally bioavailable, CNS-penetrant CGRP antagonist with good pharmacokinetic properties.
Asunto(s)
Dipéptidos/química , Dipéptidos/farmacología , Quinazolinonas/química , Quinazolinonas/farmacología , Receptores de Péptido Relacionado con el Gen de Calcitonina/agonistas , Tiazolidinedionas/química , Tiazolidinedionas/farmacología , Urea/análogos & derivados , Animales , Azepinas/química , Azepinas/farmacocinética , Péptido Relacionado con Gen de Calcitonina/metabolismo , Dipéptidos/farmacocinética , Humanos , Imidazoles/química , Imidazoles/farmacocinética , Concentración 50 Inhibidora , Trastornos Migrañosos/tratamiento farmacológico , Estructura Molecular , Peso Molecular , Piperazinas , Unión Proteica/efectos de los fármacos , Quinazolinas/química , Quinazolinas/farmacocinética , Quinazolinonas/farmacocinética , Ratas , Tiazolidinedionas/farmacocinética , Urea/química , Urea/farmacocinética , Urea/farmacologíaRESUMEN
The identification of a novel series of Aurora kinase inhibitors and exploitation of their SAR is described. Replacement of the initial quinazoline core with a pyrimidine scaffold and modification of substituents led to a series of very potent inhibitors of cellular proliferation. MK-0457 (VX-680) has been assessed in Phase II clinical trials in patients with treatment-refractory chronic myelogenous leukemia (CML) or Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ALL) containing the T315I mutation.
Asunto(s)
Piperazinas/química , Inhibidores de Proteínas Quinasas/química , Proteínas Serina-Treonina Quinasas/antagonistas & inhibidores , Aurora Quinasas , Línea Celular Tumoral , Simulación por Computador , Cristalografía por Rayos X , Diseño de Fármacos , Humanos , Leucemia Mielógena Crónica BCR-ABL Positiva/tratamiento farmacológico , Proteínas Mutantes/antagonistas & inhibidores , Proteínas Mutantes/metabolismo , Piperazinas/farmacología , Inhibidores de Proteínas Quinasas/síntesis química , Inhibidores de Proteínas Quinasas/farmacología , Proteínas Serina-Treonina Quinasas/metabolismo , Relación Estructura-ActividadRESUMEN
Aryl CH hydrogen bonds play an important role in the binding of several analogues of a pyrazol-3-ylquinazolin-4-ylamine inhibitor of glycogen synthase kinase 3 (GSK3). Understanding the importance of these CH...O and CH...N hydrogen bonds allowed the design of a novel quinazolin-4-ylthiazol-2-ylamine inhibitor of GSK3 with a structurally confirmed CH...O hydrogen bond to the protein.