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1.
J Med Chem ; 67(2): 1225-1242, 2024 Jan 25.
Artigo em Inglês | MEDLINE | ID: mdl-38228402

RESUMO

Interleukin-1 receptor-associated kinase 4 (IRAK4) plays a critical role in innate inflammatory processes. Here, we describe the discovery of two clinical candidate IRAK4 inhibitors, BAY1834845 (zabedosertib) and BAY1830839, starting from a high-throughput screening hit derived from Bayer's compound library. By exploiting binding site features distinct to IRAK4 using an in-house docking model, liabilities of the original hit could surprisingly be overcome to confer both candidates with a unique combination of good potency and selectivity. Favorable DMPK profiles and activity in animal inflammation models led to the selection of these two compounds for clinical development in patients.


Assuntos
Ensaios de Triagem em Larga Escala , Indazóis , Quinases Associadas a Receptores de Interleucina-1 , Piridinas , Animais , Humanos , Sítios de Ligação , Inflamação
2.
J Med Chem ; 63(20): 11854-11881, 2020 10 22.
Artigo em Inglês | MEDLINE | ID: mdl-32960053

RESUMO

The growth of uterine fibroids is sex hormone-dependent and commonly associated with highly incapacitating symptoms. Most treatment options consist of the control of these hormonal effects, ultimately blocking proliferative estrogen signaling (i.e., oral contraceptives/antagonization of human gonadotropin-releasing hormone receptor [hGnRH-R] activity). Full hGnRH-R blockade, however, results in menopausal symptoms and affects bone mineralization, thus limiting treatment duration or demanding estrogen add-back approaches. To overcome such issues, we aimed to identify novel, small-molecule hGnRH-R antagonists. This led to the discovery of compound BAY 1214784, an orally available, potent, and selective hGnRH-R antagonist. Altering the geminal dimethylindoline core of the initial hit compound to a spiroindoline system significantly improved GnRH-R antagonist potencies across several species, mandatory for a successful compound optimization in vivo. In a first-in-human study in postmenopausal women, once daily treatment with BAY 1214784 effectively lowered plasma luteinizing hormone levels by up to 49%, at the same time being associated with low pharmacokinetic variability and good tolerability.


Assuntos
Descoberta de Drogas , Indóis/farmacologia , Pós-Menopausa , Receptores LHRH/antagonistas & inibidores , Compostos de Espiro/farmacologia , Administração Oral , Animais , Células CACO-2 , Relação Dose-Resposta a Droga , Feminino , Hepatócitos/química , Hepatócitos/metabolismo , Humanos , Indóis/administração & dosagem , Indóis/química , Microssomos Hepáticos/química , Microssomos Hepáticos/metabolismo , Estrutura Molecular , Ratos , Ratos Wistar , Receptores LHRH/metabolismo , Compostos de Espiro/administração & dosagem , Compostos de Espiro/química , Relação Estrutura-Atividade
3.
J Med Chem ; 62(22): 10321-10341, 2019 11 27.
Artigo em Inglês | MEDLINE | ID: mdl-31670515

RESUMO

The human luteinizing hormone receptor (hLH-R) is a member of the glycoprotein hormone family of G-protein-coupled receptors (GPCRs), activated by luteinizing hormone (hLH) and essentially involved in the regulation of sex hormone production. Thus, hLH-R represents a valid target for the treatment of sex hormone-dependent cancers and diseases (polycystic ovary syndrome, uterine fibroids, endometriosis) as well as contraception. Screening of the Bayer compound library led to the discovery of tetrahydrothienopyridine derivatives as novel, small-molecule (SMOL) hLH-R inhibitors and to the development of BAY-298, the first nanomolar hLH-R antagonist reducing sex hormone levels in vivo. Further optimization of physicochemical, pharmacokinetic, and safety parameters led to the identification of BAY-899 with an improved in vitro profile and proven efficacy in vivo. BAY-298 and BAY-899 serve as valuable tool compounds to study hLH-R signaling in vitro and to interfere with the production of sex hormones in vivo.


Assuntos
Estradiol/sangue , Naftiridinas/química , Receptores do LH/antagonistas & inibidores , Administração Oral , Animais , Disponibilidade Biológica , Relação Dose-Resposta a Droga , Canal de Potássio ERG1/metabolismo , Feminino , Células da Granulosa/efeitos dos fármacos , Ensaios de Triagem em Larga Escala , Humanos , Masculino , Camundongos , Microssomos Hepáticos/efeitos dos fármacos , Ovulação/efeitos dos fármacos , Ovulação/genética , Progesterona/sangue , Ratos Wistar , Receptores do FSH/antagonistas & inibidores , Receptores do LH/metabolismo , Relação Estrutura-Atividade , Testosterona/sangue
4.
J Med Chem ; 62(24): 11194-11217, 2019 12 26.
Artigo em Inglês | MEDLINE | ID: mdl-31746599

RESUMO

The P2X4 receptor is a ligand-gated ion channel that is expressed on a variety of cell types, especially those involved in inflammatory and immune processes. High-throughput screening led to a new class of P2X4 inhibitors with substantial CYP 3A4 induction in human hepatocytes. A structure-guided optimization with respect to decreased pregnane X receptor (PXR) binding was started. It was found that the introduction of larger and more polar substituents on the ether linker led to less PXR binding while maintaining the P2X4 inhibitory potency. This translated into significantly reduced CYP 3A4 induction for compounds 71 and 73. Unfortunately, the in vivo pharmacokinetic (PK) profiles of these compounds were insufficient for the desired profile in humans. However, BAY-1797 (10) was identified and characterized as a potent and selective P2X4 antagonist. This compound is suitable for in vivo studies in rodents, and the anti-inflammatory and anti-nociceptive effects of BAY-1797 were demonstrated in a mouse complete Freund's adjuvant (CFA) inflammatory pain model.


Assuntos
Acetamidas/farmacologia , Indutores do Citocromo P-450 CYP3A/farmacologia , Citocromo P-450 CYP3A/metabolismo , Descoberta de Drogas , Inflamação/tratamento farmacológico , Dor/tratamento farmacológico , Antagonistas do Receptor Purinérgico P2X/farmacologia , Receptores Purinérgicos P2X4/química , Acetamidas/química , Animais , Apoptose , Proliferação de Células , Células Cultivadas , Indutores do Citocromo P-450 CYP3A/química , Indução Enzimática , Feminino , Regulação da Expressão Gênica , Humanos , Inflamação/metabolismo , Inflamação/patologia , Ligantes , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Dor/metabolismo , Dor/patologia , Antagonistas do Receptor Purinérgico P2X/química , Ratos , Ratos Wistar
5.
Endocrinology ; 153(4): 1725-33, 2012 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-22334713

RESUMO

Estrogen replacement is an effective therapy of postmenopausal symptoms such as hot flushes, bone loss, and vaginal dryness. Undesired estrogen effects are the stimulation of uterine and mammary gland epithelial cell proliferation as well as hepatic estrogenicity. In this study, we examined the influence of different estradiol release kinetics on tissue responsivity in ovariectomized (OVX) rats. Pulsed release kinetics was achieved by ip or sc administration of estradiol dissolved in physiological saline containing 10% ethanol (EtOH/NaCl) whereas continuous release kinetics was achieved by sc injection of estradiol dissolved in benzylbenzoate/ricinus oil (1+4, vol/vol). Initial 3-d experiments in OVX rats showed that pulsed ip estradiol administration had profoundly reduced stimulatory effects on the uterus and the liver compared with continuous release kinetics. On the other hand, both administration forms prevented severe vaginal atrophy. Based on these results, we compared the effects of pulsed (sc in EtOH/NaCl) vs. continuous (sc in benzylbenzoate/ricinus oil) estradiol release kinetics on bone, uterus, mammary gland, and liver in a 4-month study in OVX rats. Ovariectomy-induced bone loss was prevented by both administration regimes. However, pulsed estradiol resulted in lower uterine weight, reduced induction of hepatic gene expression, and reduced mammary epithelial hyperplasia relative to continuous estradiol exposure. We conclude that organ responsivity is influenced by different hormone release kinetics, a fact that might be exploited to reduce undesired estradiol effects in postmenopausal women.


Assuntos
Osso e Ossos/efeitos dos fármacos , Estradiol/farmacologia , Estradiol/farmacocinética , Fígado/efeitos dos fármacos , Ovariectomia , Útero/efeitos dos fármacos , Animais , Atrofia/induzido quimicamente , Densidade Óssea/efeitos dos fármacos , Osso e Ossos/patologia , Relação Dose-Resposta a Droga , Estradiol/administração & dosagem , Terapia de Reposição de Estrogênios/efeitos adversos , Feminino , Hiperplasia/induzido quimicamente , Injeções , Fígado/patologia , Glândulas Mamárias Animais/efeitos dos fármacos , Glândulas Mamárias Animais/patologia , Modelos Animais , Ratos , Ratos Wistar , Fatores de Tempo , Útero/patologia , Vagina/efeitos dos fármacos , Vagina/patologia
6.
Endocrinology ; 149(10): 4846-56, 2008 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-18566127

RESUMO

The classical estrogen receptor (ER) mediates genomic as well as rapid nongenomic estradiol responses. In case of genomic responses, the ER acts as a ligand-dependent transcription factor that regulates gene expression in estrogen target tissues. In contrast, nongenomic effects are initiated at the plasma membrane and lead to rapid activation of cytoplasmic signal transduction pathways. Recently, an orphan G protein-coupled receptor, GPR30, has been claimed to bind to and to signal in response to estradiol. GPR30 therefore might mediate some of the nongenomic estradiol effects. The present study was performed to clarify the controversy about the subcellular localization of GPR30 and to gain insight into the in vivo function of this receptor. In transiently transfected cells as well as cells endogenously expressing GPR30, we confirmed that the receptor localized to the endoplasmic reticulum. However, using radioactive estradiol, we observed only saturable, specific binding to the classical ER but not to GPR30. Estradiol stimulation of cells expressing GPR30 had no impact on intracellular cAMP or calcium levels. To elucidate the physiological role of GPR30, we performed in vivo experiments with estradiol and G1, a compound that has been claimed to act as selective GPR30 agonist. In two classical estrogen target organs, the uterus and the mammary gland, G1 did not show any estrogenic effect. Taken together, we draw the conclusion that GPR30 is still an orphan receptor.


Assuntos
Retículo Endoplasmático/metabolismo , Estradiol/metabolismo , Receptores Acoplados a Proteínas G/metabolismo , Animais , Células COS , Cálcio/metabolismo , Chlorocebus aethiops , AMP Cíclico/metabolismo , Estradiol/farmacologia , Feminino , Proteínas de Fluorescência Verde/genética , Humanos , Glândulas Mamárias Animais/efeitos dos fármacos , Glândulas Mamárias Animais/crescimento & desenvolvimento , Glândulas Mamárias Animais/fisiologia , Camundongos , Ovariectomia , Ligação Proteica/fisiologia , Receptores de Estrogênio , Receptores Acoplados a Proteínas G/agonistas , Receptores Acoplados a Proteínas G/genética , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/fisiologia , Transfecção , Útero/efeitos dos fármacos , Útero/crescimento & desenvolvimento , Útero/fisiologia
7.
Nat Med ; 12(8): 873; author reply 873-4, 2006 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-16892024
8.
Mol Cell Biol ; 24(19): 8642-8, 2004 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-15367682

RESUMO

Human epididymal protein 6 (HE6; also known as GPR64) is an orphan member of the LNB-7TM (B(2)) subfamily of G-protein-coupled receptors. Family members are characterized by the dual presence of a secretin-like (type II) seven-transmembrane (7TM) domain and a long cell adhesion-like extracellular domain. HE6 is specifically expressed within the efferent ductules and the initial segment of the epididymis, ductal systems involved in spermatozoon maturation. Here, we report that targeted deletion of the 7TM domain of the murine HE6 gene results in male infertility. Mutant mice reveal a dysregulation of fluid reabsorbtion within the efferent ductules, leading to a backup of fluid accumulation in the testis and a subsequent stasis of spermatozoa within the efferent ducts. The fertility phenotype of HE6 knockout mice identifies this receptor as a potential nonsteroidal, nontesticular target for future male contraceptives and identifies an in vivo function for a member of this unusual gene family.


Assuntos
Epididimo/patologia , Infertilidade Masculina/genética , Receptores Acoplados a Proteínas G/genética , Animais , Northern Blotting , Epididimo/metabolismo , Deleção de Genes , Infertilidade Masculina/metabolismo , Infertilidade Masculina/patologia , Masculino , Camundongos , Camundongos Knockout , RNA Mensageiro/metabolismo , Receptores Acoplados a Proteínas G/metabolismo , Testículo/patologia
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