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1.
J Med Chem ; 67(10): 8122-8140, 2024 May 23.
Artigo em Inglês | MEDLINE | ID: mdl-38712838

RESUMO

Multiple sclerosis (MS) is a chronic disease with an underlying pathology characterized by inflammation-driven neuronal loss, axonal injury, and demyelination. Bruton's tyrosine kinase (BTK), a nonreceptor tyrosine kinase and member of the TEC family of kinases, is involved in the regulation, migration, and functional activation of B cells and myeloid cells in the periphery and the central nervous system (CNS), cell types which are deemed central to the pathology contributing to disease progression in MS patients. Herein, we describe the discovery of BIIB129 (25), a structurally distinct and brain-penetrant targeted covalent inhibitor (TCI) of BTK with an unprecedented binding mode responsible for its high kinome selectivity. BIIB129 (25) demonstrated efficacy in disease-relevant preclinical in vivo models of B cell proliferation in the CNS, exhibits a favorable safety profile suitable for clinical development as an immunomodulating therapy for MS, and has a low projected total human daily dose.


Assuntos
Tirosina Quinase da Agamaglobulinemia , Encéfalo , Esclerose Múltipla , Inibidores de Proteínas Quinases , Tirosina Quinase da Agamaglobulinemia/antagonistas & inibidores , Tirosina Quinase da Agamaglobulinemia/metabolismo , Esclerose Múltipla/tratamento farmacológico , Humanos , Animais , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/uso terapêutico , Inibidores de Proteínas Quinases/farmacocinética , Inibidores de Proteínas Quinases/química , Encéfalo/metabolismo , Camundongos , Descoberta de Drogas , Encefalomielite Autoimune Experimental/tratamento farmacológico , Ratos , Relação Estrutura-Atividade , Proliferação de Células/efeitos dos fármacos , Feminino
2.
JCI Insight ; 5(8)2020 04 23.
Artigo em Inglês | MEDLINE | ID: mdl-32208384

RESUMO

Heart failure (HF) remains a grievous illness with poor prognosis even with optimal care. The apelin receptor (APJ) counteracts the pressor effect of angiotensin II, attenuates ischemic injury, and has the potential to be a novel target to treat HF. Intravenous administration of apelin improves cardiac function acutely in patients with HF. However, its short half-life restricts its use to infusion therapy. To identify a longer acting APJ agonist, we conducted a medicinal chemistry campaign, leading to the discovery of potent small-molecule APJ agonists with comparable activity to apelin by mimicking the C-terminal portion of apelin-13. Acute infusion increased systolic function and reduced systemic vascular resistance in 2 rat models of impaired cardiac function. Similar results were obtained in an anesthetized but not a conscious canine HF model. Chronic oral dosing in a rat myocardial infarction model reduced myocardial collagen content and improved diastolic function to a similar extent as losartan, a RAS antagonist standard-of-care therapy, but lacked additivity with coadministration. Collectively, this work demonstrates the feasibility of developing clinical, viable, potent small-molecule agonists that mimic the endogenous APJ ligand with more favorable drug-like properties and highlights potential limitations for APJ agonism for this indication.


Assuntos
Receptores de Apelina/agonistas , Coração/efeitos dos fármacos , Animais , Cães , Descoberta de Drogas , Insuficiência Cardíaca , Peptídeos e Proteínas de Sinalização Intercelular , Ratos
3.
ACS Med Chem Lett ; 9(7): 757-760, 2018 Jul 12.
Artigo em Inglês | MEDLINE | ID: mdl-30034614

RESUMO

GPR40 (FFA1) is a G-protein-coupled receptor, primarily expressed in pancreatic islets and enteroendocrine L-cells, and, when activated, elicits increased insulin secretion only in the presence of elevated glucose levels. We recently reported the discovery of AM-1638 (2), a full agonist of GPR40. Herein, we present further structure-activity relationships progressing from AM-1638 (2) to AM-6226 (14) that possesses a profile acceptable for dosing cynomolgus monkeys. The GPR40 full agonist AM-6226 (14) is the first molecule to display significant glucose lowering in cynomolgus monkeys providing additional evidence that GPR40 full agonists afford access to a powerful mechanism for maintaining glycemic control.

4.
ACS Med Chem Lett ; 7(7): 666-70, 2016 Jul 14.
Artigo em Inglês | MEDLINE | ID: mdl-27437074

RESUMO

Two 1-(4-aryl-5-alkyl-pyridin-2-yl)-3-methylurea glucokinase activators were identified with robust in vivo efficacy. These two compounds possessed higher solubilities than the previously identified triaryl compounds (i.e., AM-2394). Structure-activity relationship studies are presented along with relevant pharmacokinetic and in vivo data.

5.
ACS Med Chem Lett ; 7(7): 714-8, 2016 Jul 14.
Artigo em Inglês | MEDLINE | ID: mdl-27437083

RESUMO

Glucokinase (GK) catalyzes the phosphorylation of glucose to glucose-6-phosphate. We present the structure-activity relationships leading to the discovery of AM-2394, a structurally distinct GKA. AM-2394 activates GK with an EC50 of 60 nM, increases the affinity of GK for glucose by approximately 10-fold, exhibits moderate clearance and good oral bioavailability in multiple animal models, and lowers glucose excursion following an oral glucose tolerance test in an ob/ob mouse model of diabetes.

6.
J Med Chem ; 58(1): 480-511, 2015 Jan 08.
Artigo em Inglês | MEDLINE | ID: mdl-25469863

RESUMO

The development and optimization of a series of quinolinylpurines as potent and selective PI3Kδ kinase inhibitors with excellent physicochemical properties are described. This medicinal chemistry effort led to the identification of 1 (AMG319), a compound with an IC50 of 16 nM in a human whole blood assay (HWB), excellent selectivity over a large panel of protein kinases, and a high level of in vivo efficacy as measured by two rodent disease models of inflammation.


Assuntos
Adenosina/farmacologia , Doenças Autoimunes/prevenção & controle , Classe I de Fosfatidilinositol 3-Quinases/antagonistas & inibidores , Inflamação/prevenção & controle , Inibidores de Proteínas Quinases/farmacologia , Quinolinas/farmacologia , Adenosina/química , Adenosina/metabolismo , Animais , Células Cultivadas , Classe I de Fosfatidilinositol 3-Quinases/química , Classe I de Fosfatidilinositol 3-Quinases/metabolismo , Cristalografia por Raios X , Modelos Animais de Doenças , Descoberta de Drogas , Feminino , Humanos , Camundongos Endogâmicos BALB C , Camundongos Transgênicos , Modelos Químicos , Modelos Moleculares , Estrutura Molecular , Ligação Proteica , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/metabolismo , Estrutura Terciária de Proteína , Quinolinas/química , Quinolinas/metabolismo , Ratos Endogâmicos Lew , Células Sf9 , Relação Estrutura-Atividade
7.
ACS Med Chem Lett ; 5(12): 1284-9, 2014 Dec 11.
Artigo em Inglês | MEDLINE | ID: mdl-25516785

RESUMO

Glucokinase (GK) activators represent a class of type 2 diabetes therapeutics actively pursued due to the central role that GK plays in regulating glucose homeostasis. Herein we report a novel C5-alkyl-2-methylurea-substituted pyridine series of GK activators derived from our previously reported thiazolylamino pyridine series. Our efforts in optimizing potency, enzyme kinetic properties, and metabolic stability led to the identification of compound 26 (AM-9514). This analogue showed a favorable combination of in vitro potency, enzyme kinetic properties, acceptable pharmacokinetic profiles in preclinical species, and robust efficacy in a rodent PD model.

8.
ACS Med Chem Lett ; 4(6): 551-5, 2013 Jun 13.
Artigo em Inglês | MEDLINE | ID: mdl-24900707

RESUMO

GPR40 (FFAR1 or FFA1) is a target of high interest being pursued to treat type II diabetes due to its unique mechanism leading to little risk of hypoglycemia. We recently reported the discovery of AM-1638 (2), a potent full agonist of GPR40. In this report, we present the discovery of GPR40 full agonists containing conformationally constrained tricyclic spirocycles and their structure-activity relationships leading to more potent agonists such as AM-5262 (26) with improved rat PK profile and general selectivity profile. AM-5262 enhanced glucose stimulated insulin secretion (mouse and human islets) and improved glucose homeostasis in vivo (OGTT in HF/STZ mice) when compared to AM-1638.

9.
ACS Med Chem Lett ; 3(9): 726-30, 2012 Sep 13.
Artigo em Inglês | MEDLINE | ID: mdl-24900539

RESUMO

GPR40 (FFA1) is a G-protein-coupled receptor, primarily expressed in pancreatic islets, the activation of which elicits increased insulin secretion only in the presence of elevated glucose levels. A potent, orally bioavailable small molecule GPR40 agonist is hypothesized to be an effective antidiabetic posing little or no risk of hypoglycemia. We recently reported the discovery of AMG 837 (1), a potent partial agonist of GPR40. Herein, we present the optimization from the GPR40 partial agonist 1 to the structurally and pharmacologically distinct GPR40 full agonist AM-1638 (21). Moreover, we demonstrate the improved in vivo efficacy that GPR40 full agonist 21 exhibits in BDF/DIO mice as compared to partial agonist 1.

10.
J Med Chem ; 55(17): 7667-85, 2012 Sep 13.
Artigo em Inglês | MEDLINE | ID: mdl-22876881

RESUMO

Structure-based rational design led to the synthesis of a novel series of potent PI3K inhibitors. The optimized pyrrolopyridine analogue 63 was a potent and selective PI3Kß/δ dual inhibitor that displayed suitable physicochemical properties and pharmacokinetic profile for animal studies. Analogue 63 was found to be efficacious in animal models of inflammation including a keyhole limpet hemocyanin (KLH) study and a collagen-induced arthritis (CIA) disease model of rheumatoid arthritis. These studies highlight the potential therapeutic value of inhibiting both the PI3Kß and δ isoforms in the treatment of a number of inflammatory diseases.


Assuntos
Descoberta de Drogas , Avaliação Pré-Clínica de Medicamentos , Inibidores de Fosfoinositídeo-3 Quinase , Inibidores de Proteínas Quinases/farmacologia , Modelos Moleculares
11.
ACS Med Chem Lett ; 1(9): 488-92, 2010 Dec 09.
Artigo em Inglês | MEDLINE | ID: mdl-24900236

RESUMO

In an effort to develop potent, orally bioavailable compounds for the treatment of neoplastic diseases, we developed a class of dual VEGFR-2 kinase and tubulin inhibitors. Targeting the VEGFR receptor kinase and tubulin structure allows for inhibition of both tumor cells and tumor vasculature. Previously, a combination of two compounds, a VEGF receptor tyrosine kinase inhibitor and tubulin agent, was demonstrated to produce an enhanced antitumor response in animal studies. We have reaffirmed their results, with the added benefit that both activities are found in one compound.

12.
Bioorg Med Chem Lett ; 16(5): 1191-6, 2006 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-16377187

RESUMO

Oxadiazole derivatives were synthesized and evaluated for their ability to inhibit tubulin polymerization and to cause mitotic arrest in tumor cells. The most potent compounds inhibited tubulin polymerization at concentrations below 1 microM. Lead analogs caused mitotic arrest of A431 human epidermoid cells and cells derived from multi-drug resistant tumors (10, EC(50)=7.8 nM). Competition for the colchicine binding site and pharmacokinetic properties of selected potent compounds were also investigated and are reported herein, along with structure-activity relationships for this novel series of antimitotic agents.


Assuntos
Antimitóticos/síntese química , Antimitóticos/farmacologia , Oxidiazóis/química , Oxidiazóis/farmacologia , Tubulina (Proteína)/química , Tubulina (Proteína)/metabolismo , Animais , Antimitóticos/química , Antimitóticos/classificação , Biopolímeros/química , Biopolímeros/metabolismo , Linhagem Celular Tumoral , Humanos , Concentração Inibidora 50 , Camundongos , Estrutura Molecular , Oxidiazóis/síntese química , Oxidiazóis/classificação , Conformação Proteica/efeitos dos fármacos , Relação Estrutura-Atividade
13.
Bioorg Med Chem Lett ; 15(23): 5154-9, 2005 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-16198562

RESUMO

A novel triazole-containing chemical series was shown to inhibit tubulin polymerization and cause cell cycle arrest in A431 cancer cells with EC(50) values in the single digit nanomolar range. Binding experiments demonstrated that representative active compounds of this class compete with colchicine for its binding site on tubulin. The syntheses and structure-activity relationship studies for the triazole derivatives are described herein.


Assuntos
Antineoplásicos/química , Antineoplásicos/farmacologia , Triazóis/química , Triazóis/farmacologia , Moduladores de Tubulina/química , Moduladores de Tubulina/farmacologia , Antineoplásicos/síntese química , Humanos , Microtúbulos/efeitos dos fármacos , Estrutura Molecular , Relação Estrutura-Atividade , Triazóis/síntese química , Moduladores de Tubulina/síntese química , Células Tumorais Cultivadas
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