RESUMO
In this manuscript, we report a series of chiral 6-azaspiro[2.5]octanes and related spirocycles as highly potent and selective antagonists of the muscarinic acetylcholine receptor subtype 4 (mAChR4). Chiral separation and subsequent X-ray crystallographic analysis of early generation analogs revealed the R enantiomer to possess excellent human and rat M4 potency, and further structure-activity relationship (SAR) studies on this chiral scaffold led to the discovery of VU6015241 (compound 19). Compound 19 is characterized by high M4 potency and selectivity across multiple species, excellent aqueous solubility, and moderate brain exposure in rodents after intraperitoneal administration.
Assuntos
Antagonistas Muscarínicos/farmacologia , Receptor Muscarínico M4/antagonistas & inibidores , Relação Dose-Resposta a Droga , Humanos , Estrutura Molecular , Antagonistas Muscarínicos/síntese química , Antagonistas Muscarínicos/química , Receptor Muscarínico M4/metabolismo , Relação Estrutura-AtividadeRESUMO
This Letter describes the synthesis and optimization of a series of heteroaryl-pyrrolidinone positive allosteric modulators (PAMs) of the muscarinic acetylcholine receptor M1 (mAChR M1). Through the continued optimization of M1 PAM tool compound VU0453595, with a focus on replacement of the 6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one with a wide variety of alternative 4,5-dihydropyrrolo-fused heteroaromatics, the generation of M1 PAMs with structurally novel chemotypes is disclosed. Two compounds from these subseries, 8b (VU6005610) and 20a (VU6005852), show robust selectivity for the M1 mAChR, and no M1 agonism. Both compounds have favorable preliminary PK profiles in vitro;8b additionally demonstrates high brain exposure in a rodent IV cassette model.
Assuntos
Descoberta de Drogas , Pirrolidinonas/farmacologia , Receptor Muscarínico M1/agonistas , Regulação Alostérica/efeitos dos fármacos , Animais , Relação Dose-Resposta a Droga , Humanos , Estrutura Molecular , Pirrolidinonas/síntese química , Pirrolidinonas/química , Ratos , Relação Estrutura-AtividadeRESUMO
This Letter details our efforts to develop novel tricyclic M4 PAM scaffolds with improved pharmacological properties. This endeavor involved a "tie-back" strategy to replace the 3-amino-4,6-dimethylthieno[2,3-b]pyridine-2-carboxamide core which lead to the discovery of two novel tricyclic cores: a 7,9-dimethylpyrido[3',2':4,5]thieno[3,2-d]pyrimidine core and 2,4-dimethylthieno[2,3-b:5,4-c']dipyridine core. Both tricyclic cores displayed low nanomolar potency against the human M4 receptor.
Assuntos
Descoberta de Drogas , Pirimidinas/farmacologia , Receptor Muscarínico M4/antagonistas & inibidores , Relação Dose-Resposta a Droga , Humanos , Estrutura Molecular , Pirimidinas/síntese química , Pirimidinas/química , Receptor Muscarínico M4/metabolismo , Relação Estrutura-AtividadeRESUMO
The activin-like kinases are a family of kinases that play important roles in a variety of disease states. Of this class of kinases, ALK2, has been shown by a gain-of-function to be the primary driver of the childhood skeletal disease fibrodysplasia ossificans progressiva (FOP) and more recently the pediatric cancer diffuse intrinsic pontine glioma (DIPG). Herein, we report our efforts to identify a novel imidazo[1,2-a]pyridine scaffold as potent inhibitors of ALK2 with good in vivo pharmacokinetic properties suitable for future animal studies.
Assuntos
Receptores de Ativinas Tipo I/antagonistas & inibidores , Glioma Pontino Intrínseco Difuso/tratamento farmacológico , Miosite Ossificante/tratamento farmacológico , Inibidores de Proteínas Quinases/síntese química , Quinolinas/síntese química , Animais , Criança , Descoberta de Drogas , Humanos , Imidazolinas/química , Microssomos Hepáticos/efeitos dos fármacos , Mutação , Inibidores de Proteínas Quinases/farmacocinética , Piridinas/química , Quinolinas/farmacocinética , Ratos , Transdução de Sinais , Relação Estrutura-AtividadeRESUMO
This Letter details our efforts to discover structurally unique M4 PAMs containing 5,6-heteroaryl ring systems. In an attempt to improve the DMPK profiles of the 2,3-dimethyl-2H-indazole-5-carboxamide and 1-methyl-1H-benzo[d][1,2,3]triazole-6-carboxamide cores, we investigated a plethora of core replacements. This exercise identified a novel 2,3-dimethylimidazo[1,2-a]pyrazine-6-carboxamide core that provided improved M4 PAM activity and CNS penetration.
Assuntos
Imidazóis/química , Pirazinas/química , Receptor Muscarínico M4/química , Regulação Alostérica , Desenho de Fármacos , Avaliação Pré-Clínica de Medicamentos , Humanos , Imidazóis/metabolismo , Cinética , Ligação Proteica , Pirazinas/metabolismo , Receptor Muscarínico M4/metabolismo , Relação Estrutura-AtividadeRESUMO
This Letter details our efforts to develop new M4 PAM scaffolds with improved pharmacological properties. This endeavor involved replacing the 3,4-dimethylpyridazine core with two novel cores: a 2,3-dimethyl-2H-indazole-5-carboxamide core or a 1-methyl-1H-benzo[d][1,2,3]triazole-6-carboxamide core. Due to shallow SAR, these cores were further evolved into two unique tricyclic cores: an 8,9-dimethyl-8H-pyrazolo[3,4-h]quinazoline core and an 1-methyl-1H-[1,2,3]triazolo[4,5-h]quinazoline core. Both tricyclic cores displayed low nanomolar potency against both human and rat M4.
Assuntos
Piridazinas/química , Quinazolinas/química , Receptor Muscarínico M4/química , Triazóis/química , Regulação Alostérica , Animais , Desenho de Fármacos , Meia-Vida , Humanos , Concentração Inibidora 50 , Piridazinas/metabolismo , Piridazinas/farmacocinética , Quinazolinas/metabolismo , Quinazolinas/farmacocinética , Ratos , Receptor Muscarínico M4/metabolismo , Relação Estrutura-Atividade , Triazóis/metabolismo , Triazóis/farmacocinéticaRESUMO
Glucose-stimulated insulin secretion from pancreatic ß-cells is controlled by ATP-regulated potassium (KATP) channels composed of Kir6.2 and sulfonylurea receptor 1 (SUR1) subunits. The KATP channel-opener diazoxide is FDA-approved for treating hyperinsulinism and hypoglycemia but suffers from off-target effects on vascular KATP channels and other ion channels. The development of more specific openers would provide critically needed tool compounds for probing the therapeutic potential of Kir6.2/SUR1 activation. Here, we characterize a novel scaffold activator of Kir6.2/SUR1 that our group recently discovered in a high-throughput screen. Optimization efforts with medicinal chemistry identified key structural elements that are essential for VU0071063-dependent opening of Kir6.2/SUR1. VU0071063 has no effects on heterologously expressed Kir6.1/SUR2B channels or ductus arteriole tone, indicating it does not open vascular KATP channels. VU0071063 induces hyperpolarization of ß-cell membrane potential and inhibits insulin secretion more potently than diazoxide. VU0071063 exhibits metabolic and pharmacokinetic properties that are favorable for an in vivo probe and is brain penetrant. Administration of VU0071063 inhibits glucose-stimulated insulin secretion and glucose-lowering in mice. Taken together, these studies indicate that VU0071063 is a more potent and specific opener of Kir6.2/SUR1 than diazoxide and should be useful as an in vitro and in vivo tool compound for investigating the therapeutic potential of Kir6.2/SUR1 expressed in the pancreas and brain.
Assuntos
Ativação do Canal Iônico/efeitos dos fármacos , Canais de Potássio Corretores do Fluxo de Internalização/metabolismo , Receptores de Sulfonilureias/metabolismo , Xantinas/farmacologia , Xantinas/farmacocinética , Animais , Canal Arterial/efeitos dos fármacos , Canal Arterial/fisiologia , Glucose/farmacologia , Células HEK293 , Humanos , Secreção de Insulina/efeitos dos fármacos , Células Secretoras de Insulina/citologia , Células Secretoras de Insulina/efeitos dos fármacos , Células Secretoras de Insulina/metabolismo , Camundongos , Relação Estrutura-Atividade , Vasodilatação/efeitos dos fármacos , Xantinas/químicaRESUMO
This letter describes a diversity-oriented library approach to rapidly assess diverse heterocycles as bioisosteric replacements for a metabolically labile amide moiety within a series of mGlu7 negative allosteric modulators (NAMs). SAR rapidly honed in on either a 1,2,4- or 1,3,4-oxadizaole ring system as an effective bioisostere for the amide. Further optimization of the southern region of the mGlu7 NAM chemotype led to the discovery of VU6019278, a potent mGlu7 NAM (IC50â¯=â¯501â¯nM, 6.3% L-AP4 Min) with favorable plasma protein binding (rat fuâ¯=â¯0.10), low predicted hepatic clearance (rat CLhepâ¯=â¯27.7â¯mL/min/kg) and high CNS penetration (rat Kpâ¯=â¯4.9, Kp,uuâ¯=â¯0.65).
Assuntos
Amidas/química , Compostos Heterocíclicos/química , Receptores de Glutamato Metabotrópico/química , Regulação Alostérica , Animais , Sistema Nervoso Central/metabolismo , Hepatócitos/citologia , Hepatócitos/metabolismo , Compostos Heterocíclicos/metabolismo , Concentração Inibidora 50 , Pirazóis/química , Pirazóis/metabolismo , Ratos , Receptores de Glutamato Metabotrópico/metabolismo , Relação Estrutura-AtividadeRESUMO
This letter describes a focused, multi-dimensional optimization campaign around BL-1249, a fenamate class non-steroidal anti-inflammatory and a known activator of the K2P potassium channels TREK-1 (K2P2.1) and TREK-2 (K2P10.1). While BL-1249 has been widely profiled in vitro as a dual TREK-1/2 activator, poor physicochemical and DMPK properties have precluded a deeper understanding of the therapeutic potential of these key K2P channels across a broad spectrum of peripheral and central human disease. Here, we report multi-dimensional SAR that led to a novel TREK-1/2 dual activator chemotype, exemplified by ONO-2960632/VU6011992, with improved DMPK properties, representing a new lead for further optimization towards robust in vivo tool compounds.
Assuntos
Canais de Potássio de Domínios Poros em Tandem/metabolismo , Tetra-Hidronaftalenos/uso terapêutico , Tetrazóis/uso terapêutico , Humanos , Tetra-Hidronaftalenos/farmacologia , Tetrazóis/farmacologiaRESUMO
This Letter details our efforts to replace the 2,4-dimethylquinoline carboxamide core of our previous M4 PAM series, which suffered from high predicted hepatic clearance and protein binding. A scaffold hopping exercise identified a novel 3,4-dimethylcinnoline carboxamide core that provided good M4 PAM activity and improved clearance and protein binding profiles.
Assuntos
Receptor Muscarínico M4/química , Regulação Alostérica , Amidas/química , Azetidinas/química , Benzeno/química , Estrutura Molecular , Ligação Proteica , Pirazinas/química , Piridinas/química , Pirimidinas/química , Relação Estrutura-AtividadeRESUMO
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.
Assuntos
Amidas/farmacologia , Receptor Muscarínico M4/antagonistas & inibidores , Regulação Alostérica/efeitos dos fármacos , Amidas/síntese química , Amidas/química , Relação Dose-Resposta a Droga , Humanos , Ligação de Hidrogênio , Ligantes , Estrutura Molecular , Receptor Muscarínico M4/metabolismo , Relação Estrutura-AtividadeRESUMO
This letter describes progress towards an M4 PAM preclinical candidate that resulted in the discovery of VU6005806/AZN-00016130. While the thieno[2,3-c]pyridazine core has been a consistent feature of key M4 PAMs, no work had previously been reported with respect to alternate functionality at the C3 position of the pyridazine ring. Here, we detail new chemistry and analogs that explored this region, and quickly led to VU6005806/AZN-00016130, which was profiled as a putative candidate. While, the ß-amino carboxamide moiety engendered solubility limited absorption in higher species precluding advancement (or requiring extensive pharmaceutical sciences formulation), VU6005806/AZN-00016130 represents a new, high quality preclinical in vivo probe.
Assuntos
Regulação Alostérica/imunologia , Receptor Muscarínico M4/imunologia , Estrutura Molecular , Relação Estrutura-AtividadeRESUMO
This letter describes the first account of the chemical optimization (SAR and DMPK profiling) of a new series of mGlu4 positive allosteric modulators (PAMs), leading to the identification of VU0652957 (VU2957, Valiglurax), a compound profiled as a preclinical development candidate. Here, we detail the challenges faced in allosteric modulator programs (e.g., steep SAR, as well as subtle structural changes affecting overall physiochemical/DMPK properties and CNS penetration).
Assuntos
Descoberta de Drogas , Compostos Heterocíclicos com 2 Anéis/farmacologia , Isoquinolinas/farmacologia , Miotonina Proteína Quinase/antagonistas & inibidores , Receptores de Glutamato Metabotrópico/metabolismo , Regulação Alostérica/efeitos dos fármacos , Relação Dose-Resposta a Droga , Compostos Heterocíclicos com 2 Anéis/química , Humanos , Isoquinolinas/química , Estrutura Molecular , Miotonina Proteína Quinase/metabolismo , Relação Estrutura-AtividadeRESUMO
This letter describes progress towards an M4 PAM preclinical candidate inspired by an unexpected aldehyde oxidase (AO) metabolite of a novel, CNS penetrant thieno[2,3-c]pyridine core to an equipotent, non-CNS penetrant thieno[2,3-c]pyrdin-7(6H)-one core. Medicinal chemistry design efforts yielded two novel tricyclic cores that enhanced M4 PAM potency, regained CNS penetration, displayed favorable DMPK properties and afforded robust in vivo efficacy in reversing amphetamine-induced hyperlocomotion in rats.
Assuntos
Aldeído Oxidase/metabolismo , Miotonia Congênita/metabolismo , Receptor Muscarínico M4/metabolismo , Animais , Descoberta de Drogas , Humanos , Ratos , Relação Estrutura-AtividadeRESUMO
This letter describes the chemical optimization of a new series of M1 positive allosteric modulators (PAMs) based on a novel benzomorpholine core, developed via iterative parallel synthesis, and culminating in the highly utilized rodent in vivo tool compound, VU0486846 (7), devoid of adverse effect liability. This is the first report of the optimization campaign (SAR and DMPK profiling) that led to the discovery of VU0486846 and details all of the challenges faced in allosteric modulator programs (both steep and flat SAR, as well as subtle structural changes affecting CNS penetration and overall physiochemical and DMPK properties).
Assuntos
Descoberta de Drogas , Morfolinas/farmacologia , Pirazóis/farmacologia , Receptor Muscarínico M1/agonistas , Animais , Células CHO , Cricetulus , Humanos , Estrutura Molecular , Morfolinas/síntese química , Morfolinas/química , Pirazóis/síntese química , Pirazóis/química , Ratos , Relação Estrutura-AtividadeRESUMO
Previous reports from our laboratory disclosed the structure and activity of a novel 1H-pyrazolo[4,3-b]pyridine-3-amine scaffold (VU8506) which showed excellent potency, selectivity and in vivo efficacy in preclinical rodent models of Parkinson's disease. Unfortunately, this compound suffered from significant CYP1A2 induction as measured through upstream AhR activation (125-fold) and thus was precluded from further advancement in chronic studies. Herein, we report a new scaffold developed recently which was systematically studied in order to mitigate the CYP1A2 liabilities presented in the earlier scaffolds. We have identified a novel structure that maintains the potency and selectivity of other mGlu4 PAMs, leading to 9i (hmGlu4 EC50â¯=â¯43â¯nM; AhR activationâ¯=â¯2.3-fold).
Assuntos
Indutores do Citocromo P-450 CYP1A2/farmacologia , Citocromo P-450 CYP1A2/biossíntese , Descoberta de Drogas , Pirazóis/química , Pirazóis/farmacologia , Piridinas/química , Piridinas/farmacologia , Receptores de Glutamato Metabotrópico/efeitos dos fármacos , Regulação Alostérica/efeitos dos fármacos , Animais , Antiparkinsonianos/farmacologia , Indução Enzimática/efeitos dos fármacos , Humanos , Ratos , Receptores de Glutamato Metabotrópico/metabolismo , Relação Estrutura-AtividadeRESUMO
This letter describes the synthesis and structure activity relationship (SAR) studies of structurally novel M4 antagonists, based on a 4,6-disubstituted core, identified from a high-throughput screening campaign. A multi-dimensional optimization effort enhanced potency at both human and rat M4 (IC50s<300nM), with no substantial species differences noted. Moreover, CNS penetration proved attractive for this series (brain:plasma Kp,uu=0.87), while other DMPK attributes were addressed in the course of the optimization effort, providing low in vivo clearance in rat (CLp=5.37mL/min/kg). Surprisingly, this series displayed pan-muscarinic antagonist activity across M1-5, despite the absence of the prototypical basic or quaternary amine moiety, thus offering a new chemotype from which to develop a next generation of pan-muscarinic antagonist agents.
Assuntos
Antagonistas Muscarínicos/síntese química , Pirimidinas/química , Receptor Muscarínico M4/antagonistas & inibidores , Animais , Encéfalo/metabolismo , Humanos , Concentração Inibidora 50 , Antagonistas Muscarínicos/química , Antagonistas Muscarínicos/farmacocinética , Ligação Proteica , Pirimidinas/síntese química , Pirimidinas/farmacocinética , Ratos , Receptor Muscarínico M4/metabolismo , Receptores Muscarínicos/química , Receptores Muscarínicos/genética , Receptores Muscarínicos/metabolismo , Proteínas Recombinantes/biossíntese , Proteínas Recombinantes/química , Relação Estrutura-AtividadeRESUMO
This letter describes the synthesis and structure activity relationship (SAR) studies of structurally novel M4 antagonists, based on a 3-(4-aryl/heteroarylsulfonyl)piperazin-1-yl)-6-(piperidin-1-yl)pyridazine core, identified from a high-throughput screening campaign. A multi-dimensional optimization effort enhanced potency at human M4 (hM4 IC50s<200nM), with only moderate species differences noted, and with enantioselective inhibition. Moreover, CNS penetration proved attractive for this series (rat brain:plasma Kp=2.1, Kp,uu=1.1). Despite the absence of the prototypical mAChR antagonist basic or quaternary amine moiety, this series displayed pan-muscarinic antagonist activity across M1-5 (with 9- to 16-fold functional selectivity at best). This series further expands the chemical diversity of mAChR antagonists.
Assuntos
Encéfalo/metabolismo , Antagonistas Muscarínicos/farmacologia , Antagonistas Muscarínicos/farmacocinética , Piridazinas/farmacologia , Piridazinas/farmacocinética , Receptor Muscarínico M4/antagonistas & inibidores , Animais , Encéfalo/efeitos dos fármacos , Células CHO , Cricetulus , Humanos , Antagonistas Muscarínicos/química , Piperazina , Piperazinas/química , Piperazinas/farmacocinética , Piperazinas/farmacologia , Piridazinas/química , Ratos , Receptor Muscarínico M4/metabolismo , Relação Estrutura-AtividadeRESUMO
This Letter details our efforts to replace the 3-amino moiety, an essential pharmacophore for M4 PAM activity in most M4 PAMs to date, within the thieno[2,3-b]pyridine core, as the ß-amino carboxamide motif has been shown to engender poor solubility, varying degrees of P-gp efflux and represents a structural alert. A scaffold hopping exercise identified a novel 2,4-dimethylquinoline carboxamide core that provided M4 PAM activity and good CNS penetration without an amino moiety. In addition, MacMillan photoredox catalysis chemistry was essential for construction of the 2,4-dimethylquinoline core.
Assuntos
Amidas/química , Receptor Muscarínico M4/metabolismo , Regulação Alostérica , Amidas/síntese química , Amidas/farmacocinética , Animais , Encéfalo/metabolismo , Avaliação Pré-Clínica de Medicamentos , Meia-Vida , Ligação Proteica , Piridinas/química , Ratos , Ratos Sprague-Dawley , Receptor Muscarínico M4/química , Relação Estrutura-AtividadeRESUMO
This Letter details the discovery and subsequent optimization of a novel M4 PAM scaffold based on an 6-fluoro-4-(piperidin-1-yl)quinoline-3-carbonitrile core, which represents a distinct departure from the classical M4 PAM chemotypes. Optimized compounds in this series demonstrated improved M4 PAM potency on both human and rat M4 (4 to 5-fold relative to HTS hit), and displayed attractive physicochemical and DMPK profiles, including good CNS penetration (rat brain:plasma Kp=5.3, Kp,uu=2.4; MDCK-MDR1 (P-gp) ER=1.1).