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1.
Bioorg Med Chem Lett ; 29(20): 126673, 2019 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-31519373

RESUMO

A series of benzothiazoles with a cyano group was synthesized and evaluated as endothelial lipase (EL) inhibitors for the potential treatment of cardiovascular diseases. Efforts to reduce molecular weight and polarity in the series led to improved physicochemical properties of these compounds, as well as selectivity for EL over hepatic lipase (HL). As a benchmark compound, 8i demonstrated potent EL activity, an acceptable absorption, distribution, metabolism and elimination (ADME) profile and pharmacokinetic (PK) exposure which allowed further evaluation in preclinical animal efficacy studies.

2.
Bioorg Med Chem Lett ; 29(19): 126604, 2019 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-31445854

RESUMO

This manuscript describes the discovery of a series of macrocyclic inhibitors of FXIa with oral bioavailability. Assisted by structure based drug design and ligand bound X-ray crystal structures, the group linking the P1 moiety to the macrocyclic core was modified with the goal of reducing H-bond donors to improve pharmacokinetic performance versus 9. This effort resulted in the discovery of several cyclic P1 linkers, exemplified by 10, that are constrained mimics of the bioactive conformation displayed by the acrylamide linker of 9. These cyclic P1 linkers demonstrated enhanced bioavailability and improved potency.

4.
J Med Chem ; 62(16): 7400-7416, 2019 Aug 22.
Artigo em Inglês | MEDLINE | ID: mdl-31246024

RESUMO

In an effort to identify novel antithrombotics, we have investigated protease-activated receptor 4 (PAR4) antagonism by developing and evaluating a tool compound, UDM-001651, in a monkey thrombosis model. Beginning with a high-throughput screening hit, we identified an imidazothiadiazole-based PAR4 antagonist chemotype. Detailed structure-activity relationship studies enabled optimization to a potent, selective, and orally bioavailable PAR4 antagonist, UDM-001651. UDM-001651 was evaluated in a monkey thrombosis model and shown to have robust antithrombotic efficacy and no prolongation of kidney bleeding time. This combination of excellent efficacy and safety margin strongly validates PAR4 antagonism as a promising antithrombotic mechanism.

5.
Bioorg Med Chem Lett ; 29(15): 1918-1921, 2019 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-31176700

RESUMO

A low level of high density lipoprotein (HDL) is an independent risk factor for cardiovascular disease. HDL reduces inflammation and plays a central role in reverse cholesterol transport, where cholesterol is removed from peripheral tissues and atherosclerotic plaque. One approach to increase plasma HDL is through inhibition of endothelial lipase (EL). EL hydrolyzes phospholipids in HDL resulting in reduction of plasma HDL. A series of benzothiazole sulfone amides was optimized for EL inhibition potency, lipase selectivity and improved pharmacokinetic profile leading to the identification of Compound 32. Compound 32 was evaluated in a mouse pharmacodynamic model and found to show no effect on HDL cholesterol level despite achieving targeted plasma exposure (Ctrough > 15 fold over mouse plasma EL IC50 over 4 days).

6.
Bioorg Med Chem Lett ; 2018 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-30348490

RESUMO

Endothelial lipase (EL) inhibitors have been shown to elevate HDL-C levels in pre-clinical murine models and have potential benefit in prevention and treatment of cardiovascular diseases. Modification of the 1-ethyl-3-hydroxy-1,5-dihydro-2H-pyrrol-2-one (DHP) lead, 1, led to the discovery of a series of potent tetrahydropyrimidinedione (THP) EL inhibitors. Synthesis and SAR studies including modification of the amide group, together with changes on the pyrimidinone core led to a series of arylcycloalkyl, indanyl, and tetralinyl substituted 5-amino or 5-hydroxypyrimidinedione-4-carboxamides. Several compounds were advanced to PK evaluation. Among them, compound 4a was one of the most potent with measurable ELHDL hSerum potency and compound 3g demonstrated the best overall pharmacokinetic parameters.

7.
ACS Med Chem Lett ; 9(7): 673-678, 2018 Jul 12.
Artigo em Inglês | MEDLINE | ID: mdl-30034599

RESUMO

Screening of a small set of nonselective lipase inhibitors against endothelial lipase (EL) identified a potent and reversible inhibitor, N-(3-(3,4-dichlorophenyl)propyl)-3-hydroxy-1-methyl-2-oxo-1,2-dihydropyridine-4-carboxamide (5; EL IC50 = 61 nM, ELHDL IC50 = 454 nM). Deck mining identified a related hit, N-(3-(3,4-dichlorophenyl)propyl)-4-hydroxy-1-methyl-5-oxo-2,5-dihydro-1H-pyrrole-3-carboxamide (6a; EL IC50 = 41 nM, ELHDL IC50 = 1760 nM). Both compounds were selective against lipoprotein lipase (LPL) but nonselective versus hepatic lipase (HL). Optimization of compound 6a for EL inhibition using HDL as substrate led to N-(4-(3,4-dichlorophenyl)butan-2-yl)-1-ethyl-4-hydroxy-5-oxo-2,5-dihydro-1H-pyrrole-3-carboxamide (7c; EL IC50 = 148 nM, ELHDL IC50 = 218 nM) having improved PK over compound 6a, providing a tool molecule to test for the ability to increase HDL-cholesterol (HDL-C) levels in vivo using a reversible EL inhibitor. Compound 7c did not increase HDL-C in vivo despite achieving plasma exposures targeted on the basis of enzyme activity and protein binding demonstrating the need to develop more physiologically relevant in vitro assays to guide compound progression for in vivo evaluation.

8.
J Med Chem ; 61(17): 7425-7447, 2018 Sep 13.
Artigo em Inglês | MEDLINE | ID: mdl-29775297

RESUMO

With the introduction of thrombin and factor Xa inhibitors to the oral anticoagulant market, significant improvements in both efficacy and safety have been achieved. Early clinical and preclinical data suggest that inhibitors of factor XIa can provide a still safer alternative, with expanded efficacy for arterial indications. This Perspective provides an overview of target rationale and details of the discovery and development of inhibitors of factor XIa as next generation antithrombotic agents.

11.
J Med Chem ; 60(23): 9703-9723, 2017 Dec 14.
Artigo em Inglês | MEDLINE | ID: mdl-29077405

RESUMO

Factor XIa (FXIa) is a blood coagulation enzyme that is involved in the amplification of thrombin generation. Mounting evidence suggests that direct inhibition of FXIa can block pathologic thrombus formation while preserving normal hemostasis. Preclinical studies using a variety of approaches to reduce FXIa activity, including direct inhibitors of FXIa, have demonstrated good antithrombotic efficacy without increasing bleeding. On the basis of this potential, we targeted our efforts at identifying potent inhibitors of FXIa with a focus on discovering an acute antithrombotic agent for use in a hospital setting. Herein we describe the discovery of a potent FXIa clinical candidate, 55 (FXIa Ki = 0.7 nM), with excellent preclinical efficacy in thrombosis models and aqueous solubility suitable for intravenous administration. BMS-962212 is a reversible, direct, and highly selective small molecule inhibitor of FXIa.


Assuntos
Anticoagulantes/química , Anticoagulantes/uso terapêutico , Fator XIa/antagonistas & inibidores , Isoquinolinas/química , Isoquinolinas/uso terapêutico , Trombose/tratamento farmacológico , para-Aminobenzoatos/química , para-Aminobenzoatos/uso terapêutico , Animais , Anticoagulantes/farmacocinética , Anticoagulantes/farmacologia , Coagulação Sanguínea/efeitos dos fármacos , Cristalografia por Raios X , Cães , Descoberta de Drogas , Fator XIa/química , Fator XIa/metabolismo , Humanos , Isoquinolinas/farmacocinética , Isoquinolinas/farmacologia , Masculino , Simulação de Acoplamento Molecular , Coelhos , Ratos , Bibliotecas de Moléculas Pequenas/química , Bibliotecas de Moléculas Pequenas/farmacocinética , Bibliotecas de Moléculas Pequenas/farmacologia , Bibliotecas de Moléculas Pequenas/uso terapêutico , Trombose/sangue , para-Aminobenzoatos/farmacocinética , para-Aminobenzoatos/farmacologia
12.
Bioorg Med Chem Lett ; 27(17): 4056-4060, 2017 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-28780160

RESUMO

A series of macrocyclic factor XIa (FXIa) inhibitors was designed based on an analysis of the crystal structures of the acyclic phenylimidazole compounds. Further optimization using structure-based design led to inhibitors with pM affinity for FXIa, excellent selectivity against a panel of relevant serine proteases, and good potency in the activated partial thromboplastin time (aPTT) clotting assay.


Assuntos
Fator XIa/antagonistas & inibidores , Imidazóis/farmacologia , Compostos Macrocíclicos/farmacologia , Inibidores de Serino Proteinase/farmacologia , Relação Dose-Resposta a Droga , Fator XIa/metabolismo , Humanos , Imidazóis/síntese química , Imidazóis/química , Compostos Macrocíclicos/síntese química , Compostos Macrocíclicos/química , Estrutura Molecular , Inibidores de Serino Proteinase/síntese química , Inibidores de Serino Proteinase/química , Relação Estrutura-Atividade
13.
Bioorg Med Chem Lett ; 27(16): 3833-3839, 2017 08 15.
Artigo em Inglês | MEDLINE | ID: mdl-28687203

RESUMO

Optimization of macrocyclic inhibitors of FXIa is described which focused on modifications to both the macrocyclic linker and the P1 group. Increases in potency were discovered through interactions with a key hydrophobic region near the S1 prime pocket by substitution of the macrocyclic linker with small alkyl groups. Both the position of substitution and the absolute stereochemistry of the alkyl groups on the macrocyclic linker which led to improved potency varied depending on the ring size of the macrocycle. Replacement of the chlorophenyltetrazole cinnamide P1 in these optimized macrocycles reduced the polar surface area and improved the oral bioavailability for the series, albeit at the cost of a decrease in potency.


Assuntos
Amidas/farmacologia , Descoberta de Drogas , Fator XIa/antagonistas & inibidores , Compostos Macrocíclicos/farmacologia , Inibidores de Serino Proteinase/farmacologia , Amidas/síntese química , Amidas/química , Cristalografia por Raios X , Relação Dose-Resposta a Droga , Fator XIa/metabolismo , Humanos , Compostos Macrocíclicos/síntese química , Compostos Macrocíclicos/química , Modelos Moleculares , Estrutura Molecular , Inibidores de Serino Proteinase/síntese química , Inibidores de Serino Proteinase/química , Relação Estrutura-Atividade
14.
Bioorg Med Chem Lett ; 27(12): 2650-2654, 2017 06 15.
Artigo em Inglês | MEDLINE | ID: mdl-28460818

RESUMO

Factor VIIa (FVIIa) inhibitors have shown strong antithrombotic efficacy in preclinical thrombosis models with limited bleeding liabilities. Discovery of potent, orally active FVIIa inhibitors has been largely unsuccessful due to the requirement of a basic P1 group to interact with Asp189 in the S1 binding pocket, limiting their membrane permeability. We have combined recently reported neutral P1 binding substituents with a highly optimized macrocyclic chemotype to produce FVIIa inhibitors with low nanomolar potency and enhanced permeability.


Assuntos
Fator VIIa/antagonistas & inibidores , Compostos Macrocíclicos/farmacologia , Inibidores de Serino Proteinase/farmacologia , Relação Dose-Resposta a Droga , Humanos , Compostos Macrocíclicos/síntese química , Compostos Macrocíclicos/química , Estrutura Molecular , Inibidores de Serino Proteinase/síntese química , Inibidores de Serino Proteinase/química , Relação Estrutura-Atividade
15.
J Med Chem ; 60(9): 3795-3803, 2017 May 11.
Artigo em Inglês | MEDLINE | ID: mdl-28418664

RESUMO

We have recently disclosed 5-phenyl-N-(pyridin-2-ylmethyl)-2-(pyrimidin-5-yl)quinazolin-4-amine 1 as a potent IKur current blocker with selectivity versus hERG, Na and Ca channels, and an acceptable preclinical PK profile. Upon further characterization in vivo, compound 1 demonstrated an unacceptable level of brain penetration. In an effort to reduce the level of brain penetration while maintaining the overall profile, SAR was developed at the C2' position for a series of close analogues by employing hydrogen bond donors. As a result, 5-[5-phenyl-4-(pyridin-2-ylmethylamino)quinazolin-2-yl]pyridine-3-sulfonamide (25) was identified as the lead compound in this series. Compound 25 showed robust effects in rabbit and canine pharmacodynamic models and an acceptable cross-species pharmacokinetic profile and was advanced as the clinical candidate. Further optimization of 25 to mitigate pH-dependent absorption resulted in identification of the corresponding phosphoramide prodrug (29) with an improved solubility and pharmacokinetic profile.


Assuntos
Fibrilação Atrial/tratamento farmacológico , Bloqueadores dos Canais de Potássio/uso terapêutico , Quinazolinas/uso terapêutico , Bloqueadores dos Canais de Sódio/uso terapêutico , Sulfonamidas/uso terapêutico , Animais , Espectroscopia de Ressonância Magnética Nuclear de Carbono-13 , Cães , Espectrometria de Massas , Bloqueadores dos Canais de Potássio/farmacologia , Espectroscopia de Prótons por Ressonância Magnética , Quinazolinas/química , Quinazolinas/farmacologia , Coelhos , Bloqueadores dos Canais de Sódio/farmacologia , Relação Estrutura-Atividade , Sulfonamidas/química , Sulfonamidas/farmacologia
16.
Sci Transl Med ; 9(371)2017 01 04.
Artigo em Inglês | MEDLINE | ID: mdl-28053157

RESUMO

Antiplatelet agents are proven efficacious treatments for cardiovascular and cerebrovascular diseases. However, the existing drugs are compromised by unwanted and sometimes life-threatening bleeding that limits drug usage or dosage. There is a substantial unmet medical need for an antiplatelet drug with strong efficacy and low bleeding risk. Thrombin is a potent platelet agonist that directly induces platelet activation via the G protein (heterotrimeric guanine nucleotide-binding protein)-coupled protease-activated receptors PAR1 and PAR4. A PAR1 antagonist is approved for clinical use, but its use is limited by a substantial bleeding risk. Conversely, the potential of PAR4 as an antiplatelet target has not been well characterized. Using anti-PAR4 antibodies, we demonstrated a low bleeding risk and an effective antithrombotic profile with PAR4 inhibition in guinea pigs. Subsequently, high-throughput screening and an extensive medicinal chemistry effort resulted in the discovery of BMS-986120, an orally active, selective, and reversible PAR4 antagonist. In a cynomolgus monkey arterial thrombosis model, BMS-986120 demonstrated potent and highly efficacious antithrombotic activity. BMS-986120 also exhibited a low bleeding liability and a markedly wider therapeutic window compared to the standard antiplatelet agent clopidogrel tested in the same nonhuman primate model. These preclinical findings define the biological role of PAR4 in mediating platelet aggregation. In addition, they indicate that targeting PAR4 is an attractive antiplatelet strategy with the potential to treat patients at a high risk of atherothrombosis with superior safety compared with the current standard of care.


Assuntos
Anticorpos/uso terapêutico , Fibrinolíticos/uso terapêutico , Hemorragia/tratamento farmacológico , Inibidores da Agregação de Plaquetas/uso terapêutico , Receptores de Trombina/antagonistas & inibidores , Administração Oral , Animais , Plaquetas/metabolismo , Cobaias , Células HEK293 , Humanos , Concentração Inibidora 50 , Macaca fascicularis , Masculino , Domínios Proteicos , Receptor PAR-1/metabolismo , Acidente Vascular Cerebral/tratamento farmacológico , Trombina/química , Trombose , Resultado do Tratamento
17.
J Med Chem ; 60(3): 1060-1075, 2017 02 09.
Artigo em Inglês | MEDLINE | ID: mdl-28085275

RESUMO

A novel series of macrocyclic FXIa inhibitors was designed based on our lead acyclic phenyl imidazole chemotype. Our initial macrocycles, which were double-digit nanomolar FXIa inhibitors, were further optimized with assistance from utilization of structure-based drug design and ligand bound X-ray crystal structures. This effort resulted in the discovery of a macrocyclic amide linker which was found to form a key hydrogen bond with the carbonyl of Leu41 in the FXIa active site, resulting in potent FXIa inhibitors. The macrocyclic FXIa series, exemplified by compound 16, had a FXIa Ki = 0.16 nM with potent anticoagulant activity in an in vitro clotting assay (aPTT EC1.5x = 0.27 µM) and excellent selectivity against the relevant blood coagulation enzymes.


Assuntos
Amidas/química , Fator XIa/antagonistas & inibidores , Compostos Macrocíclicos/farmacologia , Inibidores de Serino Proteinase/química , Inibidores de Serino Proteinase/farmacologia , Descoberta de Drogas , Ligações de Hidrogênio , Ligantes , Compostos Macrocíclicos/química , Compostos Macrocíclicos/farmacocinética , Estrutura Molecular , Inibidores de Serino Proteinase/farmacocinética
18.
ACS Med Chem Lett ; 8(1): 67-72, 2017 Jan 12.
Artigo em Inglês | MEDLINE | ID: mdl-28105277

RESUMO

Two novel series of meta-linked phenylglycine-based macrocyclic FVIIa inhibitors have been designed to improve the rodent metabolic stability and PK observed with the precursor para-linked phenylglycine macrocycles. Through iterative structure-based design and optimization, the TF/FVIIa Ki was improved to subnanomolar levels with good clotting activity, metabolic stability, and permeability.

19.
Medchemcomm ; 8(11): 2093-2099, 2017 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-30108726

RESUMO

Myeloperoxidase, a mammalian peroxidase involved in the immune system as an anti-microbial first responder, can produce hypochlorous acid in response to invading pathogens. Myeloperoxidase has been implicated in several chronic pathological diseases due to the chronic production of hypochlorous acid, as well as other reactive radical species. A high throughput screen and triaging protocol was developed to identify a reversible inhibitor of myeloperoxidase toward the potential treatment of chronic diseases such as atherosclerosis. The identification and characterization of a reversible myeloperoxidase inhibitor, 7-(benzyloxy)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-5-amine is described.

20.
ACS Med Chem Lett ; 7(12): 1077-1081, 2016 Dec 08.
Artigo em Inglês | MEDLINE | ID: mdl-27994741

RESUMO

Inhibitors of Factor VIIa (FVIIa), a serine protease in the clotting cascade, have shown strong antithrombotic efficacy in preclinical thrombosis models with minimal bleeding liabilities. Discovery of potent, orally active FVIIa inhibitors has been largely unsuccessful because known chemotypes have required a highly basic group in the S1 binding pocket for high affinity. A recently reported fragment screening effort resulted in the discovery of a neutral heterocycle, 7-chloro-3,4-dihydroisoquinolin-1(2H)-one, that binds in the S1 pocket of FVIIa and can be incorporated into a phenylglycine FVIIa inhibitor. Optimization of this P1 binding group led to the first series of neutral, permeable FVIIa inhibitors with low nanomolar potency.

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