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1.
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
3.
J Org Chem ; 80(14): 7019-32, 2015 Jul 17.
Artigo em Inglês | MEDLINE | ID: mdl-26151079

RESUMO

Clopidogrel is a prodrug anticoagulant with active metabolites that irreversibly inhibit the platelet surface GPCR P2Y12 and thus inhibit platelet activation. However, gaining an understanding of patient response has been limited due to imprecise understanding of metabolite activity and stereochemistry, and a lack of acceptable analytes for quantifying in vivo metabolite formation. Methods for the production of all bioactive metabolites of clopidogrel, their stereochemical assignment, and the development of stable analytes via three conceptually orthogonal routes are disclosed.


Assuntos
Microssomos Hepáticos/metabolismo , Piperidinas/síntese química , Inibidores da Agregação de Plaquetas/síntese química , Inibidores da Agregação de Plaquetas/metabolismo , Pró-Fármacos/síntese química , Ticlopidina/análogos & derivados , Fenômenos Biológicos , Clopidogrel , Humanos , Microssomos Hepáticos/efeitos dos fármacos , Piperidinas/química , Inibidores da Agregação de Plaquetas/química , Pró-Fármacos/química , Estereoisomerismo , Ticlopidina/síntese química , Ticlopidina/química , Ticlopidina/metabolismo
4.
Bioorg Med Chem Lett ; 24(7): 1843-5, 2014 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-24613378

RESUMO

We describe novel alkylsulfones as potent CCR2 antagonists with reduced hERG channel activity and improved pharmacokinetics over our previously described antagonists. Several of these new alkylsulfones have a profile that includes functional antagonism of CCR2, in vitro microsomal stability, and oral bioavailability. With this improved profile, we demonstrate that two of these antagonists, 2 and 12, are orally efficacious in an animal model of inflammatory recruitment.


Assuntos
Receptores CCR2/antagonistas & inibidores , Sulfonas/química , Animais , Cicloexanos , Relação Dose-Resposta a Droga , Humanos , Camundongos , Conformação Molecular , Relação Estrutura-Atividade
5.
Bioorg Med Chem Lett ; 22(19): 6181-4, 2012 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-22939233

RESUMO

We describe the design, synthesis, and evaluation of benzimidazoles as benzamide replacements within a series of trisubstituted cyclohexane CCR2 antagonists. 7-Trifluoromethylbenzimidazoles displayed potent binding and functional antagonism of CCR2 while being selective over CCR3. These benzimidazoles were also incorporated into lactam-containing antagonists, thus completely eliminating the customary bis-amide.


Assuntos
Benzimidazóis/farmacologia , Cicloexanos/química , Receptores CCR2/antagonistas & inibidores , Benzimidazóis/síntese química , Benzimidazóis/química , Relação Dose-Resposta a Droga , Desenho de Drogas , Humanos , Microssomos/efeitos dos fármacos , Estrutura Molecular , Relação Estrutura-Atividade
6.
Bioorg Med Chem Lett ; 22(9): 3311-6, 2012 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-22475558

RESUMO

We describe an isostere-driven approach to improve upon a previously-described series of capped dipeptide antagonists of CC Chemokine Receptor 2 (CCR2). Modification of the substitution around the isostere was combined with additional changes in a distal aromatic substituent to provide single-digit nanomolar antagonists of CCR2. These studies led to the identification of 18, a compound that was suitable for studies in murine models of CCR2 activity.


Assuntos
Amino Álcoois/química , Receptores CCR2/antagonistas & inibidores , Amino Álcoois/farmacologia , Animais , Disponibilidade Biológica , Camundongos
7.
Bioorg Med Chem Lett ; 21(22): 6909-15, 2011 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-21974952
8.
Bioorg Med Chem Lett ; 20(8): 2425-30, 2010 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-20346664

RESUMO

We describe the design, synthesis, and evaluation, of gamma-lactams as glycinamide replacements within a series of di- and trisubstituted cyclohexane CCR2 antagonists. The lactam-containing trisubstituted cyclohexanes proved to be more potent than the disubstituted analogs, as trisubstituted analog, lactam 13, displayed excellent activity (CCR2 binding IC(50)=1.0 nM and chemotaxis IC(50) = 0.5 nM) and improved metabolic stability over its parent glycinamide.


Assuntos
Cicloexanos/farmacologia , Glicina/análogos & derivados , Lactamas/química , Receptores CCR2/antagonistas & inibidores , Animais , Quimiotaxia/efeitos dos fármacos , Cicloexanos/química , Glicina/química , Camundongos
9.
ACS Med Chem Lett ; 1(3): 120-4, 2010 Jun 10.
Artigo em Inglês | MEDLINE | ID: mdl-24900185

RESUMO

During the course of our research efforts to develop a potent and selective γ-secretase inhibitor for the treatment of Alzheimer's disease, we investigated a series of carboxamide-substituted sulfonamides. Optimization based on potency, Notch/amyloid-ß precursor protein selectivity, and brain efficacy after oral dosing led to the discovery of 4 (BMS-708163). Compound 4 is a potent inhibitor of γ-secretase (Aß40 IC50 = 0.30 nM), demonstrating a 193-fold selectivity against Notch. Oral administration of 4 significantly reduced Aß40 levels for sustained periods in brain, plasma, and cerebrospinal fluid in rats and dogs.

10.
Bioorg Med Chem Lett ; 19(13): 3418-22, 2009 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-19481449

RESUMO

Potent sulfone-containing di- and trisubstituted cyclohexanes were synthesized and evaluated as CC chemokine receptor 2 (CCR2) antagonists. This led to the trisubstituted derivative 54, which exhibited excellent binding (CCR2 IC(50)=1.3nM) and functional antagonism (calcium flux IC(50)=0.5nM and chemotaxis IC(50)=0.2nM). The superiority of the trisubstituted scaffold was rationalized to be the result of a conformational rigidification, which provided insight into the bioactive conformation of this chemotype.


Assuntos
Cicloexanos/síntese química , Receptores CCR2/antagonistas & inibidores , Sulfonas/química , Cicloexanos/química , Cicloexanos/farmacologia , Conformação Molecular , Receptores CCR2/metabolismo , Sulfonas/síntese química
11.
Bioorg Med Chem Lett ; 19(3): 597-601, 2009 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-19131247

RESUMO

A series of trisubstituted cyclohexanes was designed, synthesized and evaluated as CC chemokine receptor 2 (CCR2) antagonists. This led to the identification of two distinct substitution patterns about the cyclohexane ring as potent and selective CCR2 antagonists. Compound 36 exhibited excellent binding (CCR2 IC(50)=2.4 nM) and functional antagonism (calcium flux IC(50)=2.0 nM and chemotaxis IC(50)=5.1 nM).


Assuntos
Química Farmacêutica/métodos , Receptores CCR2/antagonistas & inibidores , Receptores CCR2/química , Sítios de Ligação , Cálcio/química , Quimiocina CCL2/química , Quimiotaxia , Cicloexanos/química , Desenho de Drogas , Humanos , Concentração Inibidora 50 , Modelos Químicos , Estrutura Molecular , Ligação Proteica , Relação Estrutura-Atividade
12.
Bioorg Med Chem Lett ; 18(18): 5063-5, 2008 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-18722120

RESUMO

A series of cis-3,4-disubstituted piperidines was synthesized and evaluated as CC chemokine receptor 2 (CCR2) antagonists. Compound 24 emerged with an attractive profile, possessing excellent binding (CCR2 IC(50)=3.4 nM) and functional antagonism (calcium flux IC(50)=2.0 nM and chemotaxis IC(50)=5.4 nM). Studies to explore the binding of these piperidine analogs utilized a key CCR2 receptor mutant (E291A) with compound 14 and revealed a significant reliance on Glu291 for binding.


Assuntos
Ácido Glutâmico/metabolismo , Piperidinas/síntese química , Piperidinas/farmacologia , Receptores CCR2/antagonistas & inibidores , Técnicas de Química Combinatória , Ácido Glutâmico/química , Concentração Inibidora 50 , Estrutura Molecular , Piperidinas/química , Receptores CCR2/genética , Estereoisomerismo , Relação Estrutura-Atividade
13.
Drug Metab Dispos ; 36(6): 1102-10, 2008 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-18347085

RESUMO

The role of the intestine in the elimination of (2R)-2-{(3R)-3-amino-3-[4-(2-methylquinolin-4-ylmethoxy)phenyl]-2-oxopyrrolidin-1-yl}-N-hydroxy-4-methylpentanamide (DPC 333), a potent inhibitor of tissue necrosis factor alpha-converting enzyme, was investigated in mice and rats in vivo and in vitro. In Madine-Darby canine kidney cells stably transfected with P-glycoprotein (P-gp) and DPC 333, the transport from B-->A reservoirs exceeded the transport from A-->B by approximately 7-fold. In Caco-2 monolayers and isolated rat ileal mucosa, DPC 333 was transported from basolateral to apical reservoirs in a concentration-dependent, saturable manner, and transport was blocked by N-(4-[2-(1,2,3,4-tetrahydro-6,7-dimethoxy-2-isoquinolinyl)ethyl]-phenyl)-9,10-dihydro-5-methoxy-9-oxo-4-acridine carboxamide (GF120918), confirming the contribution of P-gp/breast cancer resistance protein in B-->A efflux of DPC 333. In quantitative whole body autoradiography studies with [(14)C]DPC 333 in mice and rats, radioactivity was distributed throughout the small intestine in both species. In GF120918-pretreated bile duct-cannulated rats, radioactivity in feces was reduced 60%. Using the in situ perfused rat intestine model, approximately 20% of an i.v. dose of [(14)C]DPC 333 was measured in the intestinal lumen within 3 h postdose, 12% as parent. Kinetic analysis of data suggested that excreted DPC 333 may be further metabolized in the gut. Intestinal clearance was 0.2 to 0.35 l/h/kg. The above data suggest that in the rodent the intestine serves as an organ of DPC 333 excretion, mediated in part by the transporter P-gp.


Assuntos
Membro 1 da Subfamília B de Cassetes de Ligação de ATP/metabolismo , Mucosa Intestinal/metabolismo , Quinolinas/farmacocinética , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/genética , Animais , Células CACO-2 , Linhagem Celular , Cães , Feminino , Humanos , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Quinolinas/sangue , Ratos , Ratos Sprague-Dawley , Transfecção
14.
J Med Chem ; 51(4): 721-4, 2008 Feb 28.
Artigo em Inglês | MEDLINE | ID: mdl-18232650

RESUMO

We describe the design, synthesis, and evaluation of novel disubstituted cyclohexanes as potent CCR2 antagonists. Exploratory SAR studies led to the cis-disubstituted derivative 22, which displayed excellent binding affinity for CCR2 (binding IC50 = 5.1 nM) and potent functional antagonism (calcium flux IC50 = 18 nM and chemotaxis IC 50 = 1 nM). Site-directed mutagenesis studies with 22 suggest the compound is binding near the key receptor residue Glu291, however, 22 is not reliant on Glu291 for its binding affinity.


Assuntos
Cicloexanos/síntese química , Receptores CCR2/antagonistas & inibidores , Ligação Competitiva , Cálcio/metabolismo , Quimiocina CCL2/metabolismo , Quimiotaxia de Leucócito/efeitos dos fármacos , Cicloexanos/química , Cicloexanos/farmacologia , Humanos , Técnicas In Vitro , Leucócitos Mononucleares/efeitos dos fármacos , Leucócitos Mononucleares/metabolismo , Modelos Moleculares , Mutagênese Sítio-Dirigida , Ensaio Radioligante , Receptores CCR2/genética , Estereoisomerismo , Relação Estrutura-Atividade
15.
J Pharm Sci ; 97(7): 2568-80, 2008 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-17914718

RESUMO

N-in-1 (or cassette) dosing pharmacokinetics (PK) has been used in drug discovery for rapid assessment of PK properties of new chemical entities. However, because of potential for drug-drug interactions this procedure is still controversial. This study was to retrospectively evaluate the N-in-1 dosing approach in drug discovery with an emphasis on the potential for drug-drug interactions. The systemic clearance, volume of distribution, oral bioavailability, and renal excretion of the 31 lead compounds in rats, dogs or chimpanzees were significantly correlated between the N-in-1 dosing and discrete studies with r values of 0.69, 0.91, 0.53, and 0.83 (p < 0.005 for all), respectively. PK parameters for 11 quality control compounds which were involved in 194 N-in-1 studies for screening approximately 1000 compounds had coefficient of variations of less than 70%. The intrinsic microsomal clearances generated from the N-in-1 and discrete incubations were nearly identical (r = 0.97, p < 0.0001). The intrinsic clearances of quality control compound from the N-in-1 incubations were consistent with its discrete CL(int) estimate (cv: 5.4%). Therefore, N-in-1 dosing is a useful approach in drug discovery to quickly obtain initial PK estimates. Potential drug-drug interactions that result in confounding PK estimates do not occur as frequently as expected.


Assuntos
Inibidores do Citocromo P-450 CYP3A , Desenho de Drogas , Avaliação Pré-Clínica de Medicamentos/métodos , Microssomos Hepáticos , Preparações Farmacêuticas/administração & dosagem , Farmacocinética , Animais , Disponibilidade Biológica , Citocromo P-450 CYP3A , Cães , Interações de Medicamentos , Humanos , Técnicas In Vitro , Masculino , Taxa de Depuração Metabólica , Microssomos Hepáticos/efeitos dos fármacos , Microssomos Hepáticos/enzimologia , Modelos Biológicos , Pan troglodytes , Ratos
17.
Bioorg Med Chem Lett ; 18(2): 694-9, 2008 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-18061445

RESUMO

Selective inhibitors of TNF-alpha Converting Enzyme (TACE) based on (1R,2S)-cyclopentyl, (3S,4S)-pyrrolidinyl, and (3R,4S)-tetrahydrofuranyl beta-benzamido hydroxamic acids have been synthesized and evaluated. This study has led to the discovery of novel inhibitors whose profiles include activity against TACE in an enzyme assay, potency in the suppression of LPS-stimulated TNF-alpha in human whole blood, selectivity against a panel of MMPs and oral bioavailability.


Assuntos
Proteínas ADAM/antagonistas & inibidores , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Ácidos Hidroxâmicos/química , Ácidos Hidroxâmicos/farmacologia , Proteína ADAM17 , Administração Oral , Animais , Disponibilidade Biológica , Cromatografia Líquida de Alta Pressão , Inibidores Enzimáticos/síntese química , Humanos , Ácidos Hidroxâmicos/administração & dosagem , Ácidos Hidroxâmicos/síntese química , Ácidos Hidroxâmicos/farmacocinética , Ratos , Estereoisomerismo
18.
Bioorg Med Chem Lett ; 18(2): 576-85, 2008 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-18096386

RESUMO

Conformational analysis of trans-1,2-disubstituted cyclohexane CCR3 antagonist 2 revealed that the cyclohexane linker could be replaced by an acyclic syn-alpha-methyl-beta-hydroxypropyl linker. Synthesis and biological evaluation of mono- and disubstituted propyl linkers support this conformational correlation. It was also found that the alpha-methyl group to the urea lowered protein binding and that the beta-hydroxyl group lowered affinity for CYP2D6. Ab initio calculations show that the alpha-methyl group governs the spatial orientation of three key functionalities within the molecule. alpha-Methyl-beta-hydroxypropyl urea 31 with a chemotaxis IC(50)=38 pM for eosinophils was chosen to enter clinical development for the treatment of asthma.


Assuntos
Quimiotaxia de Leucócito/efeitos dos fármacos , Eosinófilos/efeitos dos fármacos , Piperidinas/farmacologia , Receptores CCR3/antagonistas & inibidores , Ureia/análogos & derivados , Administração Oral , Animais , Inibidores das Enzimas do Citocromo P-450 , Cães , Eosinófilos/citologia , Ligações de Hidrogênio , Camundongos , Conformação Molecular , Piperidinas/química , Piperidinas/farmacocinética , Ratos , Relação Estrutura-Atividade , Ureia/química , Ureia/farmacocinética , Ureia/farmacologia
19.
Bioorg Med Chem Lett ; 17(19): 5455-61, 2007 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-17720492

RESUMO

A new series of CCR2 antagonists has been discovered that incorporates intramolecular hydrogen bonding as a strategy for rigidifying the scaffold. The structure-activity relationship was established through initial systematic modification of substitution pattern and chain length, followed by independent optimization of three different substituents (benzylamine, carboxamide, and benzamide). Several of the acyclic compounds display 10-30 nM binding affinity for CCR2. Moreover, these antagonists are able to block both MCP-1-induced Ca(2+) flux and monocyte chemotaxis, and are selective for binding to CCR2 over CCR1 and CCR3.


Assuntos
Dipeptídeos/síntese química , Dipeptídeos/farmacologia , Receptores CCR2/antagonistas & inibidores , Cálcio/metabolismo , Quimiocina CCL2/antagonistas & inibidores , Quimiocina CCL2/farmacologia , Quimiotaxia de Leucócito/efeitos dos fármacos , Ligações de Hidrogênio , Indicadores e Reagentes , Conformação Molecular , Monócitos/efeitos dos fármacos , Relação Estrutura-Atividade
20.
Drug Metab Dispos ; 35(10): 1916-25, 2007 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-17656469

RESUMO

DPC 333 ((2R)-2-((3R)-3-amino-3{4-[2-methyl-4-quinolinyl) methoxy] phenyl}-2-oxopyrrolidinyl)-N-hydroxy-4-methylpentanamide)) is a potent and selective inhibitor of tumor necrosis factor (TNF)-alpha-converting enzyme (TACE). It significantly inhibits lipopolysaccharide-induced soluble TNF-alpha production in blood from rodents, chimpanzee, and human, with IC(50) values ranging from 17 to 100 nM. In rodent models of endotoxemia, DPC 333 inhibited the production of TNF-alpha in a dose-dependent manner, with an oral ED(50) ranging from 1.1 to 6.1 mg/kg. Oral dosing of DPC 333 at 5.5 mg/kg daily for 2 weeks in a rat collagen antibody-induced arthritis model suppressed the maximal response by approximately 50%. DPC 333 was distributed widely to tissues including the synovium, the site of action for antiarthritic drugs. Pharmacokinetic and pharmacodynamic studies in chimpanzee revealed a systemic clearance of 0.4 l/h/kg, a V(ss) of 0.6 l/kg, an oral bioavailability of 17%, and an ex vivo IC(50) for the suppression of TNF-alpha production of 55 nM (n = 1). In a phase I clinical trial with male volunteers after single escalating doses of oral DPC 333, the terminal half-life was between 3 and 6 h and the ex vivo IC(50) for suppressing TNF-alpha production was 113 nM. Measurement of the suppression of TNF-alpha production ex vivo may serve as a good biomarker in evaluating the therapeutic efficacy of TACE inhibitors. Overall, the pharmacological profiles of DPC 333 support the notion that suppression of TNF-alpha with TACE inhibitors like DPC 333 may provide a novel approach in the treatment of various inflammatory diseases including rheumatoid arthritis, via control of excessive TNF-alpha production.


Assuntos
Proteínas ADAM/antagonistas & inibidores , Anti-Inflamatórios/farmacocinética , Anti-Inflamatórios/uso terapêutico , Artrite Experimental/tratamento farmacológico , Endotoxemia/tratamento farmacológico , Quinolinas/farmacocinética , Quinolinas/uso terapêutico , Proteína ADAM17 , Adulto , Animais , Anti-Inflamatórios/sangue , Artrite Experimental/sangue , Artrite Experimental/patologia , Cães , Método Duplo-Cego , Endotoxemia/sangue , Endotoxemia/induzido quimicamente , Feminino , Humanos , Lipopolissacarídeos , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Pan troglodytes , Quinolinas/sangue , Ratos , Ratos Endogâmicos , Líquido Sinovial/química , Fator de Necrose Tumoral alfa/antagonistas & inibidores , Fator de Necrose Tumoral alfa/sangue
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