RESUMEN
The exploitation of GLU988 and LYS903 residues in PARP1 as targets to design isoquinolinone (I & II) and naphthyridinone (III) analogues is described. Compounds of structure I have good biochemical and cellular potency but suffered from inferior PK. Constraining the linear propylene linker of structure I into a cyclopentene ring (II) offered improved PK parameters, while maintaining potency for PARP1. Finally, to avoid potential issues that may arise from the presence of an anilinic moiety, the nitrogen substituent on the isoquinolinone ring was incorporated as part of the bicyclic ring. This afforded a naphthyridinone scaffold, as shown in structure III. Further optimization of naphthyridinone series led to identification of a novel and highly potent PARP1 inhibitor 34, which was further characterized as preclinical candidate molecule. Compound 34 is orally bioavailable and displayed favorable pharmacokinetic (PK) properties. Compound 34 demonstrated remarkable antitumor efficacy both as a single-agent as well as in combination with chemotherapeutic agents in the BRCA1 mutant MDA-MB-436 breast cancer xenograft model. Additionally, compound 34 also potentiated the effect of agents such as temozolomide in breast cancer, pancreatic cancer and Ewing's sarcoma models.
Asunto(s)
Antineoplásicos/química , Naftiridinas/química , Poli(ADP-Ribosa) Polimerasa-1/antagonistas & inhibidores , Inhibidores de Poli(ADP-Ribosa) Polimerasas/química , Quinolonas/química , Animales , Antineoplásicos/metabolismo , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Sitios de Unión , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Semivida , Humanos , Ratones , Ratones Endogámicos BALB C , Simulación del Acoplamiento Molecular , Naftiridinas/metabolismo , Neoplasias/tratamiento farmacológico , Neoplasias/patología , Poli(ADP-Ribosa) Polimerasa-1/metabolismo , Inhibidores de Poli(ADP-Ribosa) Polimerasas/metabolismo , Inhibidores de Poli(ADP-Ribosa) Polimerasas/farmacología , Inhibidores de Poli(ADP-Ribosa) Polimerasas/uso terapéutico , Quinolonas/metabolismo , Relación Estructura-Actividad , Trasplante HeterólogoRESUMEN
α7 nicotinic acetylcholine receptor (α7 nAChR) is an extensively validated target for several neurological and psychiatric conditions namely, dementia and schizophrenia, owing to its vital roles in cognition and sensorimotor gating. Positive allosteric modulation (PAM) of α7 nAChR represents an innovative approach to amplify endogenous cholinergic signaling in a temporally restricted manner in learning and memory centers of brain. α7 nAChR PAMs are anticipated to side-step burgeoning issues observed with several clinical-stage orthosteric α7 nAChR agonists, related to selectivity, tolerance/tachyphylaxis, thus providing a novel dimension in therapeutic strategy and pharmacology of α7 nAChR ion-channel. Here we describe a novel α7 nAChR PAM, LL-00066471, which potently amplified agonist-induced Ca2+ fluxes in neuronal IMR-32 neuroblastoma cells in a α-bungarotoxin (α-BTX) sensitive manner. LL-00066471 showed excellent oral bioavailability across species (mouse, rat and dog), low clearance and good brain penetration (B/P ratio > 1). In vivo, LL-00066471 robustly attenuated cognitive deficits in both procognitive and antiamnesic paradigms of short-term episodic and recognition memory in novel object recognition task (NORT) and social recognition task (SRT), respectively. Additionally, LL-00066471 mitigated apomorphine-induced sensorimotor gating deficits in acoustic startle reflex (ASR) and enhanced antipsychotic efficacy of olanzapine in conditioned avoidance response (CAR) task. Further, LL-00066471 corrected redox-imbalances and reduced cortico-striatal infarcts in stroke model. These finding together suggest that LL-00066471 has potential to symptomatically alleviate cognitive deficits associated with dementias, attenuate sensorimotor gating deficits in schizophrenia and correct redox-imbalances in cerebrovascular disorders. Therefore, LL-00066471 presents potential for management of cognitive impairments associated with neurological and psychiatric conditions.
Asunto(s)
Conducta Animal/efectos de los fármacos , Encéfalo/efectos de los fármacos , Colinérgicos/farmacología , Cognición/efectos de los fármacos , Disfunción Cognitiva/prevención & control , Trastornos Neurológicos de la Marcha/prevención & control , Filtrado Sensorial/efectos de los fármacos , Receptor Nicotínico de Acetilcolina alfa 7/efectos de los fármacos , Animales , Encéfalo/metabolismo , Encéfalo/fisiopatología , Línea Celular Tumoral , Colinérgicos/farmacocinética , Disfunción Cognitiva/metabolismo , Disfunción Cognitiva/fisiopatología , Disfunción Cognitiva/psicología , Modelos Animales de Enfermedad , Perros , Conducta Exploratoria/efectos de los fármacos , Trastornos Neurológicos de la Marcha/metabolismo , Trastornos Neurológicos de la Marcha/fisiopatología , Trastornos Neurológicos de la Marcha/psicología , Accidente Cerebrovascular Isquémico/tratamiento farmacológico , Accidente Cerebrovascular Isquémico/metabolismo , Accidente Cerebrovascular Isquémico/fisiopatología , Masculino , Ratones Endogámicos BALB C , Prueba de Campo Abierto/efectos de los fármacos , Estrés Oxidativo/efectos de los fármacos , Ratas Sprague-Dawley , Ratas Wistar , Reflejo de Sobresalto/efectos de los fármacos , Transducción de Señal , Conducta Social , Receptor Nicotínico de Acetilcolina alfa 7/metabolismoRESUMEN
The discovery of a series of thiophenephenylsulfonamides as positive allosteric modulators (PAM) of α7 nicotinic acetylcholine receptor (α7 nAChR) is described. Optimization of this series led to identification of compound 28, a novel PAM of α7 nicotinic acetylcholine receptor (α7 nAChR). Compound 28 showed good in vitro potency, with pharmacokinetic profile across species with excellent brain penetration and residence time. Compound 28 robustly reversed the cognitive deficits in episodic/working memory in both time-delay and scopolamine-induced amnesia paradigms in the novel object and social recognition tasks, at very low dose levels. Additionally, compound 28 has shown excellent safety profile in phase 1 clinical trials and is being evaluated for efficacy and safety as monotherapy in patients with mild to moderate Alzheimer's disease.
Asunto(s)
Descubrimiento de Drogas , Agonistas Nicotínicos/farmacología , Nootrópicos/farmacología , Sulfonamidas/farmacología , Tiofenos/farmacología , Receptor Nicotínico de Acetilcolina alfa 7/agonistas , Enfermedad de Alzheimer/tratamiento farmacológico , Animales , Encéfalo/metabolismo , Ensayos Clínicos como Asunto , Estabilidad de Medicamentos , Humanos , Masculino , Estructura Molecular , Agonistas Nicotínicos/síntesis química , Agonistas Nicotínicos/farmacocinética , Nootrópicos/síntesis química , Nootrópicos/farmacocinética , Ratas Sprague-Dawley , Ratas Wistar , Relación Estructura-Actividad , Sulfonamidas/síntesis química , Sulfonamidas/farmacocinética , Tiofenos/síntesis química , Tiofenos/farmacocinéticaRESUMEN
This paper describes an efficient route for the synthesis of known and novel griseolic acid analogues 1d and 1e, respectively. The key intermediate dioxabicyclo derivative 6, with the required stereochemical orientation at C6, was obtained by rhodium acetate catalyzed reaction of d-glucose derived alpha-diazo-beta-keto ester 5 in a novel high-yielding methodology.