RESUMEN
This letter describes a focused exercise to explore the role of the ß-amino carboxamide moiety found in all of the first generation M4 PAMs and question if the NH2 group served solely to stabilize an intramolecular hydrogen bond (IMHB) and enforce planarity. To address this issue (and to potentially find a substitute for the ß-amino carboxamide that engendered P-gp and contributed to solubility liabilities), we removed the NH2, generating des-amino congeners and surveyed other functional groups in the ß-position. These modifications led to weak M4 PAMs with poor DMPK properties. Cyclization of the ß-amino carboxamide moiety by virtue of a pyrazole ring re-enforced the IMHB, led to potent (and patented) M4 PAMs, many as potent as the classical bicyclic ß-amino carboxamide analogs, but with significant CYP1A2 inhibition. Overall, this exercise indicated that the ß-amino carboxamide moiety most likely facilitates an IMHB, and is essential for M4 PAM activity within classical bicyclic M4 PAM scaffolds.
Asunto(s)
Amidas/farmacología , Receptor Muscarínico M4/antagonistas & inhibidores , Regulación Alostérica/efectos de los fármacos , Amidas/síntesis química , Amidas/química , Relación Dosis-Respuesta a Droga , Humanos , Enlace de Hidrógeno , Ligandos , Estructura Molecular , Receptor Muscarínico M4/metabolismo , Relación Estructura-ActividadRESUMEN
Herein, we report the structure-activity relationships within a series of potent, selective, and orally bioavailable muscarinic acetylcholine receptor 4 (M4) positive allosteric modulators (PAMs). Compound 6c (VU0467485) possesses robust in vitro M4 PAM potency across species and in vivo efficacy in preclinical models of schizophrenia. Coupled with an attractive DMPK profile and suitable predicted human PK, 6c (VU0467485) was evaluated as a preclinical development candidate.
RESUMEN
This letter describes the chemical optimization of a novel series of M4 positive allosteric modulators (PAMs) based on a 5-amino-thieno[2,3-c]pyridazine core, developed via iterative parallel synthesis, and culminating in the highly utilized rodent in vivo tool compound, VU0467154 (5). This is the first report of the optimization campaign (SAR and DMPK profiling) that led to the discovery of VU0467154, and details all of the challenges faced in allosteric modulator programs (steep SAR, species differences in PAM pharmacology and subtle structural changes affecting CNS penetration).
Asunto(s)
Piridazinas/farmacología , Receptor Muscarínico M4/agonistas , Tiofenos/farmacología , Animales , Humanos , Ligandos , Proteínas de Transporte de Nucleósidos/metabolismo , Piridazinas/administración & dosificación , Piridazinas/síntesis química , Piridazinas/farmacocinética , Ratas Sprague-Dawley , Relación Estructura-Actividad , Tiofenos/administración & dosificación , Tiofenos/síntesis química , Tiofenos/farmacocinéticaRESUMEN
3-Hydroxy-4-pyridinones and 5-hydroxy-4-pyrimidinones were identified as inhibitors of catechol-O-methyltransferase (COMT) in a high-throughput screen. These heterocyclic catechol mimics exhibit potent inhibition of the enzyme and an improved toxicity profile versus the marketed nitrocatechol inhibitors tolcapone and entacapone. Optimization of the series was aided by X-ray cocrystal structures of the novel inhibitors in complex with COMT and cofactors SAM and Mg(2+). The crystal structures suggest a mechanism of inhibition for these heterocyclic inhibitors distinct from previously disclosed COMT inhibitors.
RESUMEN
Positive allosteric modulators (PAMs) of the M4 muscarinic acetylcholine receptor (mAChR) represent a novel approach for the treatment of psychotic symptoms associated with schizophrenia and other neuropsychiatric disorders. We recently reported that the selective M4 PAM VU0152100 produced an antipsychotic drug-like profile in rodents after amphetamine challenge. Previous studies suggest that enhanced cholinergic activity may also improve cognitive function and reverse deficits observed with reduced signaling through the N-methyl-d-aspartate subtype of the glutamate receptor (NMDAR) in the central nervous system. Prior to this study, the M1 mAChR subtype was viewed as the primary candidate for these actions relative to the other mAChR subtypes. Here we describe the discovery of a novel M4 PAM, VU0467154, with enhanced in vitro potency and improved pharmacokinetic properties relative to other M4 PAMs, enabling a more extensive characterization of M4 actions in rodent models. We used VU0467154 to test the hypothesis that selective potentiation of M4 receptor signaling could ameliorate the behavioral, cognitive, and neurochemical impairments induced by the noncompetitive NMDAR antagonist MK-801. VU0467154 produced a robust dose-dependent reversal of MK-801-induced hyperlocomotion and deficits in preclinical models of associative learning and memory functions, including the touchscreen pairwise visual discrimination task in wild-type mice, but failed to reverse these stimulant-induced deficits in M4 KO mice. VU0467154 also enhanced the acquisition of both contextual and cue-mediated fear conditioning when administered alone in wild-type mice. These novel findings suggest that M4 PAMs may provide a strategy for addressing the more complex affective and cognitive disruptions associated with schizophrenia and other neuropsychiatric disorders.
Asunto(s)
Aprendizaje por Asociación/efectos de los fármacos , Maleato de Dizocilpina/toxicidad , Antagonistas de Aminoácidos Excitadores/toxicidad , Psicotrópicos/farmacología , Piridazinas/farmacología , Receptor Muscarínico M4/metabolismo , Tiofenos/farmacología , Anfetaminas/toxicidad , Animales , Aprendizaje por Asociación/fisiología , Encéfalo/efectos de los fármacos , Encéfalo/fisiología , Línea Celular , Estimulantes del Sistema Nervioso Central/toxicidad , Colinérgicos/síntesis química , Colinérgicos/farmacocinética , Colinérgicos/farmacología , Cricetulus , Perros , Relación Dosis-Respuesta a Droga , Humanos , Macaca fascicularis , Masculino , Ratones Endogámicos C57BL , Ratones Noqueados , Actividad Motora/efectos de los fármacos , Actividad Motora/fisiología , Psicotrópicos/síntesis química , Psicotrópicos/farmacocinética , Piridazinas/síntesis química , Piridazinas/farmacocinética , Ratas , Ratas Sprague-Dawley , Tiofenos/síntesis química , Tiofenos/farmacocinéticaRESUMEN
This Letter describes the further optimization of an MLPCN probe molecule (ML137) through the introduction of 5- and 6-membered spirocycles in place of the isatin ketone. Interestingly divergent structure-activity relationships, when compared to earlier M1 PAMs, are presented. These novel spirocycles possess improved efficacy relative to ML137, while also maintaining high selectivity for the human and rat muscarinic M1 receptor subtype.
Asunto(s)
Isatina/análogos & derivados , Receptor Muscarínico M1/antagonistas & inhibidores , Compuestos de Espiro/química , Regulación Alostérica , Animales , Humanos , Isatina/química , Isatina/metabolismo , Unión Proteica , Pirrolidinas/síntesis química , Pirrolidinas/química , Pirrolidinas/metabolismo , Ratas , Receptor Muscarínico M1/metabolismo , Relación Estructura-ActividadRESUMEN
This Letter describes the continued optimization of an MLPCN probe molecule (ML137) with a focused effort on the replacement/modification of the isatin moiety present in this highly selective M(1) PAM. A diverse range of structures were validated as viable replacements for the isatin, many of which engendered sizeable improvements in their ability to enhance the potency and efficacy of acetylcholine when compared to ML137. Muscarinic receptor subtype selectivity for the M(1) receptor was also maintained.
Asunto(s)
Isatina/análogos & derivados , Isatina/síntesis química , Receptor Muscarínico M1/efectos de los fármacos , Concentración 50 Inhibidora , Isatina/química , Isatina/farmacología , Sondas Moleculares/química , Sondas Moleculares/farmacología , Estructura Molecular , Inhibidores de la Monoaminooxidasa/farmacologíaRESUMEN
Utilizing a combination of high-throughput and multi-step synthesis, SAR in a novel series of M(1) acetylcholine receptor antagonists was rapidly established. The efforts led to the discovery the highly potent M(1) antagonists 6 (VU0431263), and 8f (VU0433670). Functional Schild analysis and radioligand displacement experiments demonstrated the competitive, orthosteric binding of these compounds; human selectivity data are presented.