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1.
J Med Chem ; 64(17): 12978-13003, 2021 09 09.
Artigo em Inglês | MEDLINE | ID: mdl-34432979

RESUMO

Receptor-interacting serine/threonine protein kinase 2 (RIPK2) is an important kinase of the innate immune system. Herein, we describe the optimization of a series of RIPK2 PROTACs which recruit members of the inhibitor of apoptosis (IAP) family of E3 ligases. Our PROTAC optimization strategy focused on reducing the lipophilicity of the early lead which resulted in the identification of analogues with improved solubility and increased human and rat microsomal stability. We identified a range of IAP binders that were successfully incorporated into potent RIPK2 PROTACs with attractive pharmacokinetic profiles. Compound 20 possessed the best overall profile with good solubility, potent degradation of RIPK2, and associated inhibition of TNFα release. A proof-of-concept study utilizing a slow release matrix demonstrated the feasibility of a long-acting parenteral formulation with >1 month duration. This represents an attractive alternative dosing paradigm to oral delivery, especially for chronic diseases where compliance can be challenging.


Assuntos
Proteína Serina-Treonina Quinase 2 de Interação com Receptor/metabolismo , Animais , Desenho de Fármacos , Regulação da Expressão Gênica/efeitos dos fármacos , Meia-Vida , Humanos , Masculino , Estrutura Molecular , Ratos , Ratos Sprague-Dawley , Ratos Wistar , Proteína Serina-Treonina Quinase 2 de Interação com Receptor/genética , Células THP-1
3.
J Pharm Sci ; 109(10): 3160-3171, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32565354

RESUMO

Receptor Interacting Protein 2 (RIP2) kinase inhibitors have been reported for therapeutic opportunities in inflammatory bowel diseases such as Ulcerative Colitis and Crohn's disease. During lead optimization, team identified 4-aminoquinoline series and several compounds from this series were investigated in rat and dog pharmacokinetic studies. While compounds such as GSKA and GSKB demonstrated acceptable pharmacokinetics in rat and dog, further progression of these compounds was halted due to adverse findings in advanced safety studies. Structurally similar analogues incorporating polarity at C-7 position of 4-aminoquinoline resulted in identification of GSKC - GSKF. Interestingly, following oral administration to rat at similar low dose, GSKC - GSKF demonstrated significantly low systemic drug exposure compared to GSKA and GSKB (3-17-fold difference). However, in dog, dose normalized oral systemic exposure for GSKC - GSKF was comparable to GSKA and GSKB (within 2-fold). A series of studies were conducted to understand the disconnect which highlighted that an intrinsic reduction in permeability and high P-glycoprotein (P-gp) efflux ratio for C-7 substituted analogues were driving pharmacokinetic disconnect between rat and dog. Oral absorption was minimally impacted in dog by P-gp mediated efflux compared to rat because the leakier gastrointestinal tract in dog likely overcomes this effect.


Assuntos
Subfamília B de Transportador de Cassetes de Ligação de ATP/metabolismo , Aminoquinolinas/farmacocinética , Administração Oral , Animais , Transporte Biológico , Cães , Permeabilidade , Ratos
4.
J Med Chem ; 62(14): 6482-6494, 2019 07 25.
Artigo em Inglês | MEDLINE | ID: mdl-31265286

RESUMO

RIP2 kinase has been identified as a key signal transduction partner in the NOD2 pathway contributing to a variety of human pathologies, including immune-mediated inflammatory diseases. Small-molecule inhibitors of RIP2 kinase or its signaling partners on the NOD2 pathway that are suitable for advancement into the clinic have yet to be described. Herein, we report our discovery and profile of the prodrug clinical compound, inhibitor 3, currently in phase 1 clinical studies. Compound 3 potently binds to RIP2 kinase with good kinase specificity and has excellent activity in blocking many proinflammatory cytokine responses in vivo and in human IBD explant samples. The highly favorable physicochemical and ADMET properties of 3 combined with high potency led to a predicted low oral dose in humans.


Assuntos
Benzotiazóis/farmacologia , Fosfatos/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Quinazolinas/farmacologia , Proteína Serina-Treonina Quinase 2 de Interação com Receptor/antagonistas & inibidores , Animais , Benzotiazóis/química , Benzotiazóis/farmacocinética , Benzotiazóis/uso terapêutico , Colite/tratamento farmacológico , Cães , Descoberta de Drogas , Humanos , Masculino , Camundongos , Simulação de Acoplamento Molecular , Fosfatos/química , Fosfatos/farmacocinética , Fosfatos/uso terapêutico , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/farmacocinética , Inibidores de Proteínas Quinases/uso terapêutico , Quinazolinas/química , Quinazolinas/farmacocinética , Quinazolinas/uso terapêutico , Ratos Sprague-Dawley , Proteína Serina-Treonina Quinase 2 de Interação com Receptor/metabolismo , Suínos , Porco Miniatura
5.
ACS Med Chem Lett ; 10(6): 857-862, 2019 Jun 13.
Artigo em Inglês | MEDLINE | ID: mdl-31223438

RESUMO

RIP1 regulates cell death and inflammation and is believed to play an important role in contributing to a variety of human pathologies, including immune-mediated inflammatory diseases and cancer. While small-molecule inhibitors of RIP1 kinase have been advanced to the clinic for inflammatory diseases and CNS indications, RIP1 inhibitors for oncology indications have yet to be described. Herein we report on the discovery and profile of GSK3145095 (compound 6). Compound 6 potently binds to RIP1 with exquisite kinase specificity and has excellent activity in blocking RIP1 kinase-dependent cellular responses. Highlighting its potential as a novel cancer therapy, the inhibitor was also able to promote a tumor suppressive T cell phenotype in pancreatic adenocarcinoma organ cultures. Compound 6 is currently in phase 1 clinical studies for pancreatic adenocarcinoma and other selected solid tumors.

6.
J Med Chem ; 62(10): 5096-5110, 2019 05 23.
Artigo em Inglês | MEDLINE | ID: mdl-31013427

RESUMO

RIP1 kinase regulates necroptosis and inflammation and may play an important role in contributing to a variety of human pathologies, including inflammatory and neurological diseases. Currently, RIP1 kinase inhibitors have advanced into early clinical trials for evaluation in inflammatory diseases such as psoriasis, rheumatoid arthritis, and ulcerative colitis and neurological diseases such as amyotrophic lateral sclerosis and Alzheimer's disease. In this paper, we report on the design of potent and highly selective dihydropyrazole (DHP) RIP1 kinase inhibitors starting from a high-throughput screen and the lead-optimization of this series from a lead with minimal rat oral exposure to the identification of dihydropyrazole 77 with good pharmacokinetic profiles in multiple species. Additionally, we identified a potent murine RIP1 kinase inhibitor 76 as a valuable in vivo tool molecule suitable for evaluating the role of RIP1 kinase in chronic models of disease. DHP 76 showed efficacy in mouse models of both multiple sclerosis and human retinitis pigmentosa.


Assuntos
Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/farmacologia , Complexo de Proteínas Formadoras de Poros Nucleares/antagonistas & inibidores , Pirazóis/síntese química , Pirazóis/farmacologia , Proteínas de Ligação a RNA/antagonistas & inibidores , Animais , Disponibilidade Biológica , Linhagem Celular , Doença Crônica , Desenho de Fármacos , Encefalomielite Autoimune Experimental/tratamento farmacológico , Inibidores Enzimáticos/farmacocinética , Haplorrinos , Ensaios de Triagem em Larga Escala , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Modelos Moleculares , Esclerose Múltipla/tratamento farmacológico , Pirazóis/farmacocinética , Ratos , Retinose Pigmentar/tratamento farmacológico , Relação Estrutura-Atividade
7.
ACS Med Chem Lett ; 9(10): 1039-1044, 2018 Oct 11.
Artigo em Inglês | MEDLINE | ID: mdl-30344914

RESUMO

RIP2 kinase was recently identified as a therapeutic target for a variety of autoimmune diseases. We have reported previously a selective 4-aminoquinoline-based RIP2 inhibitor GSK583 and demonstrated its effectiveness in blocking downstream NOD2 signaling in cellular models, rodent in vivo models, and human ex vivo disease models. While this tool compound was valuable in validating the biological pathway, it suffered from activity at the hERG ion channel and a poor PK/PD profile thereby limiting progression of this analog. Herein, we detail our efforts to improve both this off-target liability as well as the PK/PD profile of this series of inhibitors through modulation of lipophilicity and strengthening hinge binding ability. These efforts have led to inhibitor 7, which possesses high binding affinity for the ATP pocket of RIP2 (IC50 = 1 nM) and inhibition of downstream cytokine production in human whole blood (IC50 = 10 nM) with reduced hERG activity (14 µM).

8.
Artigo em Inglês | MEDLINE | ID: mdl-29226625

RESUMO

Therapies that suppress RIPK1 kinase activity are emerging as promising therapeutic agents for the treatment of multiple inflammatory disorders. The ability to directly measure drug binding of a RIPK1 inhibitor to its target is critical for providing insight into pharmacokinetics, pharmacodynamics, safety and clinical efficacy, especially for a first-in-class small-molecule inhibitor where the mechanism has yet to be explored. Here, we report a novel method for measuring drug binding to RIPK1 protein in cells and tissues. This TEAR1 (Target Engagement Assessment for RIPK1) assay is a pair of immunoassays developed on the principle of competition, whereby a first molecule (ie, drug) prevents the binding of a second molecule (ie, antibody) to the target protein. Using the TEAR1 assay, we have validated the direct binding of specific RIPK1 inhibitors in cells, blood and tissues following treatment with benzoxazepinone (BOAz) RIPK1 inhibitors. The TEAR1 assay is a valuable tool for facilitating the clinical development of the lead RIPK1 clinical candidate compound, GSK2982772, as a first-in-class RIPK1 inhibitor for the treatment of inflammatory disease.


Assuntos
Anticorpos/metabolismo , Inibidores de Proteínas Quinases/farmacologia , Proteína Serina-Treonina Quinases de Interação com Receptores/metabolismo , Animais , Células HT29 , Humanos , Imunoensaio , Macaca fascicularis , Masculino , Ligação Proteica/efeitos dos fármacos , Proteína Serina-Treonina Quinases de Interação com Receptores/imunologia , Bibliotecas de Moléculas Pequenas/farmacologia
9.
J Med Chem ; 60(4): 1247-1261, 2017 02 23.
Artigo em Inglês | MEDLINE | ID: mdl-28151659

RESUMO

RIP1 regulates necroptosis and inflammation and may play an important role in contributing to a variety of human pathologies, including immune-mediated inflammatory diseases. Small-molecule inhibitors of RIP1 kinase that are suitable for advancement into the clinic have yet to be described. Herein, we report our lead optimization of a benzoxazepinone hit from a DNA-encoded library and the discovery and profile of clinical candidate GSK2982772 (compound 5), currently in phase 2a clinical studies for psoriasis, rheumatoid arthritis, and ulcerative colitis. Compound 5 potently binds to RIP1 with exquisite kinase specificity and has excellent activity in blocking many TNF-dependent cellular responses. Highlighting its potential as a novel anti-inflammatory agent, the inhibitor was also able to reduce spontaneous production of cytokines from human ulcerative colitis explants. The highly favorable physicochemical and ADMET properties of 5, combined with high potency, led to a predicted low oral dose in humans.


Assuntos
Anti-Inflamatórios/química , Anti-Inflamatórios/farmacologia , Colite Ulcerativa/tratamento farmacológico , Inflamação/tratamento farmacológico , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/farmacologia , Proteína Serina-Treonina Quinases de Interação com Receptores/antagonistas & inibidores , Animais , Benzazepinas/química , Benzazepinas/farmacologia , Colite Ulcerativa/imunologia , Citocinas/imunologia , Cães , Haplorrinos , Humanos , Inflamação/imunologia , Camundongos , Simulação de Acoplamento Molecular , Coelhos , Ratos , Proteína Serina-Treonina Quinases de Interação com Receptores/imunologia , Suínos , Porco Miniatura , Fator de Necrose Tumoral alfa/imunologia
10.
J Med Chem ; 59(10): 4867-80, 2016 05 26.
Artigo em Inglês | MEDLINE | ID: mdl-27109867

RESUMO

RIP2 kinase is a central component of the innate immune system and enables downstream signaling following activation of the pattern recognition receptors NOD1 and NOD2, leading to the production of inflammatory cytokines. Recently, several inhibitors of RIP2 kinase have been disclosed that have contributed to the fundamental understanding of the role of RIP2 in this pathway. However, because they lack either broad kinase selectivity or strong affinity for RIP2, these tools have only limited utility to assess the role of RIP2 in complex environments. We present, herein, the discovery and pharmacological characterization of GSK583, a next-generation RIP2 inhibitor possessing exquisite selectivity and potency. Having demonstrated the pharmacological precision of this tool compound, we report its use in elucidating the role of RIP2 kinase in a variety of in vitro, in vivo, and ex vivo experiments, further clarifying our understanding of the role of RIP2 in NOD1 and NOD2 mediated disease pathogenesis.


Assuntos
Aminoquinolinas/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Proteína Serina-Treonina Quinase 2 de Interação com Receptor/antagonistas & inibidores , Sulfonas/farmacologia , Aminoquinolinas/sangue , Aminoquinolinas/química , Animais , Relação Dose-Resposta a Droga , Feminino , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Modelos Moleculares , Estrutura Molecular , Inibidores de Proteínas Quinases/sangue , Inibidores de Proteínas Quinases/química , Ratos , Ratos Sprague-Dawley , Proteína Serina-Treonina Quinase 2 de Interação com Receptor/metabolismo , Relação Estrutura-Atividade , Sulfonas/sangue , Sulfonas/química
11.
J Med Chem ; 59(5): 2163-78, 2016 Mar 10.
Artigo em Inglês | MEDLINE | ID: mdl-26854747

RESUMO

The recent discovery of the role of receptor interacting protein 1 (RIP1) kinase in tumor necrosis factor (TNF)-mediated inflammation has led to its emergence as a highly promising target for the treatment of multiple inflammatory diseases. We screened RIP1 against GSK's DNA-encoded small-molecule libraries and identified a novel highly potent benzoxazepinone inhibitor series. We demonstrate that this template possesses complete monokinase selectivity for RIP1 plus unique species selectivity for primate versus nonprimate RIP1. We elucidate the conformation of RIP1 bound to this benzoxazepinone inhibitor driving its high kinase selectivity and design specific mutations in murine RIP1 to restore potency to levels similar to primate RIP1. This series differentiates itself from known RIP1 inhibitors in combining high potency and kinase selectivity with good pharmacokinetic profiles in rodents. The favorable developability profile of this benzoxazepinone template, as exemplified by compound 14 (GSK'481), makes it an excellent starting point for further optimization into a RIP1 clinical candidate.


Assuntos
DNA/química , Isoxazóis/farmacologia , Oxazepinas/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Proteína Serina-Treonina Quinases de Interação com Receptores/antagonistas & inibidores , Bibliotecas de Moléculas Pequenas/farmacologia , Animais , Linhagem Celular Tumoral , Cristalografia por Raios X , Relação Dose-Resposta a Droga , Células HT29 , Humanos , Isoxazóis/síntese química , Isoxazóis/química , Camundongos , Modelos Moleculares , Estrutura Molecular , Oxazepinas/síntese química , Oxazepinas/química , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/química , Proteína Serina-Treonina Quinases de Interação com Receptores/metabolismo , Bibliotecas de Moléculas Pequenas/síntese química , Bibliotecas de Moléculas Pequenas/química , Relação Estrutura-Atividade , Células U937
12.
ACS Med Chem Lett ; 4(12): 1238-43, 2013 Dec 12.
Artigo em Inglês | MEDLINE | ID: mdl-24900635

RESUMO

Potent inhibitors of RIP1 kinase from three distinct series, 1-aminoisoquinolines, pyrrolo[2,3-b]pyridines, and furo[2,3-d]pyrimidines, all of the type II class recognizing a DLG-out inactive conformation, were identified from screening of our in-house kinase focused sets. An exemplar from the furo[2,3-d]pyrimidine series showed a dose proportional response in protection from hypothermia in a mouse model of TNFα induced lethal shock.

13.
J Pharm Sci ; 100(9): 3862-74, 2011 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-21360708

RESUMO

The purpose of this investigation was to compare selected pharmacokinetic (PK) parameters obtained by cassette and discrete dosing of compounds in rats. The concordance of PK properties obtained by the two dosing strategies was evaluated for 116 compounds representing various therapeutic programs and diverse chemical structures. The correspondence between cassette- and discrete-dosing-derived PK properties was examined semiquantitatively and qualitatively. For semiquantitative comparison, compounds with cassette-to-discrete PK parameter ratios between 0.5 and 2 (inclusive) were considered to be in agreement. For qualitative comparison, compounds were divided into three categories (low, moderate, and high) based on the value of the PK parameter; compounds that fell into the same category following cassette and discrete dosing were considered to be in agreement. Of the 116 compounds evaluated, 89%, 91%, 80%, and 91% of the compounds were semiquantitatively equivalent for the intravenous PK parameters of clearance (CL), volume of distribution (Vdss), terminal elimination plasma half-life (HL), and mean residence time (MRT), respectively, whereas 79%, 80%, 79%, and 72% were qualitatively similar for CL, Vdss, MRT, and terminal elimination plasma HL, respectively. Following oral administration, bioavailability concordance was 72% when assessed qualitatively and 78% when determined semiquantitatively. Results from these analyses indicate that a cassette dosing strategy is a viable approach to screen compounds for PK properties within a drug discovery setting.


Assuntos
Disponibilidade Biológica , Farmacocinética , Administração Oral , Animais , Cromatografia Líquida , Feminino , Meia-Vida , Masculino , Ratos , Ratos Sprague-Dawley , Espectrometria de Massas em Tandem
14.
Drug Deliv ; 17(3): 145-51, 2010 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-20136582

RESUMO

The efficacy of n-lauryl-beta-D-maltopyranoside, (dodecylmaltoside, DDM) as a permeability-enhancer for tiludronate and cromolyn (BCS Class III, water-soluble compounds with oral bioavailability < 5%) was evaluated in Caco-2 cell monolayers and rat intestinal sacs. In Caco-2 cells samples were collected over a 5-h period and transepithelial resistance (TEER) was measured concurrently. In rat intestinal sacs, samples of the test compounds and marker (Lucifer Yellow) were collected over a 40 min period; accumulation in the serosal fluid and intestinal tissue was measured. At lower concentration DDM had no effect on cromolyn permeability and a marginal increase was observed at higher concentration. Tiludronate permeability in the presence of DDM showed greater enhancement as compared to cromolyn. At higher concentration DDM appeared to cause permanent damage to the cell monolayer (irreversible change in TEER). In the intestinal tissue, DDM caused increased tissue accumulation of test compounds. This indicated that transport was not restricted to the paracellular route and damage to the intestinal tissue could not be ruled out. Based on the results obtained in this study it can be concluded that at concentrations that are non-toxic DDM appears to have a limited use to improve the oral absorption of cromolyn and tiludronate.


Assuntos
Conservadores da Densidade Óssea/farmacocinética , Cromolina Sódica/farmacocinética , Detergentes/farmacologia , Difosfonatos/farmacocinética , Glucosídeos/farmacologia , Algoritmos , Animais , Células CACO-2 , Membrana Celular/metabolismo , Corantes Fluorescentes , Humanos , Técnicas In Vitro , Absorção Intestinal/efeitos dos fármacos , Isoquinolinas , Masculino , Ratos , Ratos Sprague-Dawley
15.
Bioorg Med Chem Lett ; 20(1): 371-4, 2010 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-19926282

RESUMO

The previously reported pyrrolidine class of progesterone receptor partial agonists demonstrated excellent potency but suffered from serious liabilities including hERG blockade and high volume of distribution in the rat. The basic pyrrolidine amine was intentionally converted to a sulfonamide, carbamate, or amide to address these liabilities. The evaluation of the degree of partial agonism for these non-basic pyrrolidine derivatives and demonstration of their efficacy in an in vivo model of endometriosis is disclosed herein.


Assuntos
Pirrolidinas/química , Receptores de Progesterona/agonistas , Animais , Sítios de Ligação , Carbamatos/química , Cristalografia por Raios X , Canal de Potássio ERG1 , Endometriose/tratamento farmacológico , Canais de Potássio Éter-A-Go-Go/metabolismo , Feminino , Humanos , Pirrolidinas/síntese química , Pirrolidinas/farmacocinética , Ratos , Receptores de Progesterona/metabolismo , Sulfonamidas/química
16.
Bioorg Med Chem Lett ; 19(16): 4664-8, 2009 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-19616429

RESUMO

We have designed and synthesized a novel series of pyrrolidinones as progesterone receptor partial agonists. Compounds from this series had improved AR selectivity, rat pharmacokinetic properties, and in vivo potency compared to the lead compound. In addition, these compounds had improved selectivity against hERG channel inhibition.


Assuntos
Pirrolidinonas/química , Receptores de Progesterona/agonistas , Administração Oral , Animais , Sítios de Ligação , Descoberta de Drogas , Canais de Potássio Éter-A-Go-Go/metabolismo , Haplorrinos , Humanos , Pirrolidinonas/síntese química , Pirrolidinonas/farmacocinética , Ratos , Receptores de Progesterona/metabolismo , Relação Estrutura-Atividade
17.
Bioorg Med Chem Lett ; 19(15): 4441-5, 2009 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-19497745

RESUMO

The lead serum and glucocorticoid-related kinase 1 (SGK1) inhibitors 4-(5-phenyl-1H-pyrrolo[2,3-b]pyridin-3-yl)benzoic acid (1) and {4-[5-(2-naphthalenyl)-1H-pyrrolo[2,3-b]pyridin-3-yl]phenyl}acetic acid (2) suffer from low DNAUC values in rat, due in part to formation and excretion of glucuronic acid conjugates. These PK/glucuronidation issues were addressed either by incorporating a substituent on the 3-phenyl ring ortho to the key carboxylate functionality of 1 or by substituting on the group in between the carboxylate and phenyl ring of 2. Three of these analogs have been identified as having good SGK1 inhibition potency and have DNAUC values suitable for in vivo testing.


Assuntos
Química Farmacêutica/métodos , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/farmacologia , Proteínas Imediatamente Precoces/antagonistas & inibidores , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Administração Oral , Animais , Disponibilidade Biológica , Desenho de Fármacos , Glucocorticoides/química , Ácido Glucurônico/química , Proteínas Imediatamente Precoces/química , Concentração Inibidora 50 , Modelos Químicos , Conformação Molecular , Inibidores de Proteínas Quinases/antagonistas & inibidores , Proteínas Serina-Treonina Quinases/química , Ratos , Relação Estrutura-Atividade
18.
Bioorg Med Chem Lett ; 19(15): 4292-5, 2009 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-19487124

RESUMO

This Letter discloses a series of 2-aminothiadiazole amides as selective EP(3) receptor antagonists. SAR optimization resulted in compounds with excellent functional activity in vitro. In addition, efforts to optimize DMPK properties in the rat are discussed. These efforts have resulted in the identification of potent, selective EP(3) receptor antagonists with excellent DMPK properties suitable for in vivo studies.


Assuntos
Amidas/química , Química Farmacêutica/métodos , Receptores de Prostaglandina E/antagonistas & inibidores , Receptores de Prostaglandina E/química , Tiadiazóis/química , Administração Oral , Animais , Cães , Desenho de Fármacos , Humanos , Modelos Químicos , Estrutura Molecular , Ligação Proteica , Ratos , Ratos Sprague-Dawley , Receptores de Prostaglandina E Subtipo EP3 , Relação Estrutura-Atividade
19.
Bioorg Med Chem Lett ; 19(10): 2637-41, 2009 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-19376703

RESUMO

Two classes of amino acid-derived heterocyclic progesterone receptor ligands were developed to address the metabolic issues posed by the dimethyl amide functionality of the lead compound (1). The tetrazole-derived ligands behaved as potent partial agonists, while the 1,2,4-triazole ligands behaved as potent full agonists.


Assuntos
Receptores de Progesterona/agonistas , Tetrazóis/síntese química , Aminoácidos/química , Animais , Ratos , Receptores de Progesterona/metabolismo , Relação Estrutura-Atividade , Tetrazóis/química , Tetrazóis/farmacocinética
20.
Bioorg Med Chem Lett ; 18(13): 3716-9, 2008 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-18524591

RESUMO

Lead compound 1 was successfully redesigned to provide compounds with improved pharmacokinetic profiles for this series of human urotensin-II antagonists. Replacement of the 2-pyrrolidinylmethyl-3-phenyl-piperidine core of 1 with a substituted N-methyl-2-(1-pyrrolidinyl)ethanamine core as in compound 7 resulted in compounds with improved oral bioavailability in rats. The relationship between stereochemistry and selectivity for hUT over the kappa-opioid receptor was also explored.


Assuntos
Química Farmacêutica/métodos , Urotensinas/antagonistas & inibidores , Administração Oral , Animais , Encéfalo/metabolismo , Cromatografia Líquida de Alta Pressão , Diaminas/química , Desenho de Fármacos , Humanos , Concentração Inibidora 50 , Modelos Químicos , Ratos , Receptores Opioides kappa/química , Estereoisomerismo , Relação Estrutura-Atividade , Urotensinas/química
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