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1.
Bioorg Med Chem Lett ; 30(7): 126955, 2020 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-32035698

RESUMO

This article describes the discovery of aryl hydroxy pyrimidinones and the medicinal chemistry efforts to optimize this chemotype for potent APJ agonism. APJ is a G-protein coupled receptor whose natural agonist peptide, apelin, displays hemodynamic improvement in the cardiac function of heart failure patients. A high throughput screen was undertaken to identify small molecule hits that could be optimized to mimic the apelin in vitro response. A potent and low molecular weight aryl hydroxy pyrimidinone analog 30 was identified through optimization of an HTS hit and medicinal chemistry efforts to improve its properties.

2.
J Med Chem ; 63(4): 1660-1670, 2020 Feb 27.
Artigo em Inglês | MEDLINE | ID: mdl-31990537

RESUMO

Endothelial lipase (EL) hydrolyzes phospholipids in high-density lipoprotein (HDL) resulting in reduction in plasma HDL levels. Studies with murine transgenic, KO, or loss-of-function variants strongly suggest that inhibition of EL will lead to sustained plasma high-density lipoprotein cholesterol (HDL-C) increase and, potentially, a reduced cardiovascular disease (CVD) risk. Herein, we describe the discovery of a series of oxadiazole ketones, which upon optimization, led to the identification of compound 12. Compound 12 was evaluated in a mouse pharmacodynamics (PD) model and demonstrated a 56% increase in plasma HDL-C. In a mouse reverse cholesterol transport study, compound 12 stimulated cholesterol efflux by 53% demonstrating HDL-C functionality.

3.
Bioorg Med Chem Lett ; 30(4): 126949, 2020 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-31932224

RESUMO

The discovery of orally bioavailable FXIa inhibitors has been a challenge. Herein, we describe our efforts to address this challenge by optimization of our imidazole-based macrocyclic series. Our optimization strategy focused on modifications to the P2 prime, macrocyclic amide linker, and the imidazole scaffold. Replacing the amide of the macrocyclic linker with amide isosteres led to the discovery of substituted amine linkers which not only maintained FXIa binding affinity but also improved oral exposure in rats. Combining the optimized macrocyclic amine linker with a pyridine scaffold afforded compounds 23 and 24 that were orally bioavailable, single-digit nanomolar FXIa inhibitors with excellent selectivity against relevant blood coagulation enzymes.

4.
J Med Chem ; 63(2): 784-803, 2020 Jan 23.
Artigo em Inglês | MEDLINE | ID: mdl-31833761

RESUMO

Factor XIa (FXIa) inhibitors are promising novel anticoagulants, which show excellent efficacy in preclinical thrombosis models with minimal effects on hemostasis. The discovery of potent and selective FXIa inhibitors which are also orally bioavailable has been a challenge. Here, we describe optimization of the imidazole-based macrocyclic series and our initial progress toward meeting this challenge. A two-pronged strategy, which focused on replacement of the imidazole scaffold and the design of new P1 groups, led to the discovery of potent, orally bioavailable pyridine-based macrocyclic FXIa inhibitors. Moreover, pyridine-based macrocycle 19, possessing the phenylimidazole carboxamide P1, exhibited excellent selectivity against relevant blood coagulation enzymes and displayed antithrombotic efficacy in a rabbit thrombosis model.

5.
J Med Chem ; 62(22): 10456-10465, 2019 Nov 27.
Artigo em Inglês | MEDLINE | ID: mdl-31724863

RESUMO

The APJ receptor and its endogenous peptidic ligand apelin have been implicated as important modulators of cardiovascular function, and APJ receptor agonists may be beneficial in the treatment of heart failure. In this article, we describe the discovery of a series of biphenyl acid derivatives as potent APJ receptor agonists. Following the identification of initial high-throughput screen lead 2, successive optimization led to the discovery of lead compound 15a. Compound 15a demonstrated comparable in vitro potency to apelin-13, the endogenous peptidic ligand for the APJ receptor. In vivo, compound 15a demonstrated a dose-dependent improvement in the cardiac output in male Sprague Dawley rats with no significant changes in either mean arterial blood pressure or heart rate, consistent with the hemodynamic profile of apelin-13 in an acute pressure volume loop model.

6.
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.

7.
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.

9.
ACS Med Chem Lett ; 10(6): 911-916, 2019 Jun 13.
Artigo em Inglês | MEDLINE | ID: mdl-31223447

RESUMO

Lead optimization of the diphenylpyridylethanamine (DPPE) and triphenylethanamine (TPE) series of CETP inhibitors to improve their pharmaceutical profile is described. Polar groups at the N-terminus position in the DPPE series resulted in further improvement in potency and pharmaceutical properties concomitant with retaining the safety, efficacy, and pharmacokinetic (PK) profile. A structure-activity relationship observed in the DPPE series was extended to the corresponding analogs in the more potent TPE series, and further optimization resulted in the identification of 2-amino-N-((R)-1-(3-cyclopropoxy-4-fluorophenyl)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-2-phenylethyl)-4,4,4-trifluoro-3-hydroxy-3-(trifluoromethyl)butanamide (13). Compound 13 demonstrated no significant changes in either mean arterial blood pressure or heart rate in telemetry rats, had an excellent PK profile, and demonstrated robust efficacy in human CETP/apo-B-100 dual transgenic mice and in hamsters.

10.
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.

11.
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).

12.
Bioorg Med Chem Lett ; 28(23-24): 3721-3725, 2018 12 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.


Assuntos
Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Lipase/antagonistas & inibidores , Pirimidinonas/química , Pirimidinonas/farmacologia , Animais , HDL-Colesterol/sangue , HDL-Colesterol/metabolismo , Inibidores Enzimáticos/sangue , Inibidores Enzimáticos/síntese química , Humanos , Lipase/sangue , Lipase/metabolismo , Camundongos , Modelos Moleculares , Pirimidinonas/sangue , Pirimidinonas/síntese química , Relação Estrutura-Atividade
13.
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.

14.
J Med Chem ; 61(17): 7425-7447, 2018 09 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.


Assuntos
Anticoagulantes/química , Anticoagulantes/farmacologia , Fator XIa/antagonistas & inibidores , Anticorpos Monoclonais/química , Anticorpos Monoclonais/farmacologia , Aptâmeros de Nucleotídeos/química , Aptâmeros de Nucleotídeos/farmacologia , Domínio Catalítico , Ensaios Clínicos como Assunto , Fator XIa/química , Fator XIa/metabolismo , Humanos , Bibliotecas de Moléculas Pequenas/química , Bibliotecas de Moléculas Pequenas/farmacologia
17.
ACS Med Chem Lett ; 9(12): 1175-1180, 2018 Dec 13.
Artigo em Inglês | MEDLINE | ID: mdl-30613322

RESUMO

Myeloperoxidase (MPO) generates reactive oxygen species that potentially contribute to many chronic inflammatory diseases. A recently reported triazolopyrimidine MPO inhibitor was optimized to improve acid stability and remove methyl guanine methyl transferase (MGMT) activity. Multiple synthetic routes were explored that allowed rapid optimization of a key benzyl ether side chain. Crystal structures of inhibitors bound to the MPO active site demonstrated alternate binding modes and guided rational design of MPO inhibitors. Thioether 36 showed significant inhibition of MPO activity in an acute mouse inflammation model after oral dosing.

18.
ACS Med Chem Lett ; 9(12): 1263-1268, 2018 Dec 13.
Artigo em Inglês | MEDLINE | ID: mdl-30613337

RESUMO

Endothelial lipase (EL) selectively metabolizes high density lipoprotein (HDL) particles. Inhibition of EL has been shown to increase HDL concentration in preclinical animal models and was targeted as a potential treatment of atherosclerosis. We describe the introduction of an α-sulfone moiety to a benzothiazole series of EL inhibitors resulting in increased potency versus EL. Optimization for selectivity versus hepatic lipase and pharmacokinetic properties resulted in the discovery of 24, which showed good in vitro potency and bioavailability but, unexpectedly, did not increase HDL in the mouse pharmacodynamic model at the target plasma exposure.

19.
J Med Chem ; 60(23): 9703-9723, 2017 12 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
20.
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
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