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1.
Br J Pharmacol ; 2024 Jun 17.
Artigo em Inglês | MEDLINE | ID: mdl-38886096

RESUMO

BACKGROUND AND PURPOSE: The cannabinoid CB1 receptor has a well-established role in appetite regulation. Drugs antagonizing central CB1 receptors, most notably rimonabant, induced weight loss and improved the metabolic profile in obese individuals but were discontinued due to psychiatric side effects. However, metabolic benefits were only partially attributable to weight loss, implying a role for peripheral receptors, and peripherally restricted CB1 receptor antagonists have since been of interest. Herein, we describe the evaluation of the peripherally restricted potent CB1 receptor inverse agonists TM38837 and TM39875, with acidic functionality, which were administered daily to diet-induced obese (DIO) mice for 5 weeks at doses for which CNS-mediated effects were minimal. EXPERIMENTAL APPROACH: Compounds were tested in dose-response in acute studies to compare efficacy (gastric transport) and extent of CNS exposure (hypothermia and satiety sequence) to demonstrate peripheral restriction and select doses for the subsequent chronic DIO study. KEY RESULTS: TM38837 but not TM39875 produced considerable (26%) weight loss, linked to a sustained reduction in food intake, together with improvements in plasma markers of inflammation and glucose homeostasis. Pharmacokinetic analysis indicated high plasma and low brain levels for both compounds with high liver levels for TM38837 (but not TM39875) due to hepatic uptake. CONCLUSION AND IMPLICATIONS: Weight loss and metabolic benefits of TM38837 are likely not CNS-mediated but could be linked to enhanced liver exposure, which implicates intracellular CB1 receptors in hepatocytes as a possible driver of obesity and co-morbidities.

2.
Bioorg Med Chem Lett ; 98: 129572, 2024 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-38043690

RESUMO

Several series of diverse pyrazole-3-carboxamides functionalized with 4-methylamides, 4-methylcarboxylic acids and 4-methyltetrazoles were prepared from the corresponding 4-cyanomethylpyrazoles and investigated as Cannabinoid receptor 1 (CB1) antagonists and inverse agonists with the aim of making compounds with less CNS (Central Nervous System) mediated side-effects compared to rimonabant. The compounds were evaluated and optimized with respect to lipophilicity, solubility, CB1 potency, metabolism, distribution to brain and liver, effect on weight loss in diet-induced mice models. A few carboxylic acids and tetrazoles were selected as especially promising with the tetrazole TM38837 subsequently demonstrating impressive efficacy in various animal models of obesity, producing considerable weight loss and improvements on plasma markers of inflammation and glucose homeostasis, at doses apparently producing negligible brain exposure. TM38837 became the first peripherally restricted CB1 antagonist or inverse agonist to enter clinical trials supporting its lack of CNS effects and it is now believed that the non-CNS mediated efficacy is linked to high liver exposure. This opens opportunities to be explored in other indications such as nonalcoholic fatty liver disease (NAFLD) and steatohepatitis (NASH). Note that this is a first-time disclosure of the structure of TM38837 and other structures appearing in literature are not connected with this program.


Assuntos
Canabinoides , Agonismo Inverso de Drogas , Camundongos , Animais , Agonistas de Receptores de Canabinoides , Pirazóis/química , Canabinoides/farmacologia , Redução de Peso , Receptor CB1 de Canabinoide , Antagonistas de Receptores de Canabinoides
3.
Diabetes Obes Metab ; 20(1): 60-68, 2018 01.
Artigo em Inglês | MEDLINE | ID: mdl-28598027

RESUMO

AIM: To investigate the effects of the novel glucose-dependent insulinotropic polypeptide (GIP) analogue, ZP4165, on body weight and glycaemic control in rodents, and to investigate if ZP4165 modulates the anti-obesity and anti-hyperglycaemic effects of a glucagon-like peptide-1 (GLP-1) agonist (liraglutide). METHODS: The acute insulinotropic effect of ZP4165 was investigated in rats during an oral glucose tolerance test. The long-term effects of ZP4165 on body weight and glycaemic control, either alone or in combination with liraglutide, were assessed in diet-induced obese mice and diabetic db/db mice. RESULTS: ZP4165 showed insulinotropic action in rats. The GIP analogue did not alter the body weight of obese mice but enhanced GLP-1-induced weight loss. In diabetic mice, 4 weeks' dosing with ZP4165 reduced glycated haemoglobin levels vs vehicle by an extent similar to the GLP-1 agonist. CONCLUSIONS: ZP4165 potentiated the anti-obesity effect of a GLP-1 agonist in obese mice and improved glycaemic control in diabetic mice. These studies support further investigation of dual-incretin therapy as a more effective treatment option than mono GLP-1 medication for type 2 diabetes mellitus and obesity.


Assuntos
Fármacos Antiobesidade/uso terapêutico , Diabetes Mellitus Tipo 2/tratamento farmacológico , Polipeptídeo Inibidor Gástrico/análogos & derivados , Polipeptídeo Inibidor Gástrico/uso terapêutico , Hiperglicemia/prevenção & controle , Hipoglicemiantes/uso terapêutico , Obesidade/tratamento farmacológico , Receptores dos Hormônios Gastrointestinais/agonistas , Animais , Fármacos Antiobesidade/sangue , Fármacos Antiobesidade/farmacocinética , Fármacos Antiobesidade/farmacologia , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/metabolismo , Desenho de Fármacos , Quimioterapia Combinada , Polipeptídeo Inibidor Gástrico/farmacocinética , Polipeptídeo Inibidor Gástrico/farmacologia , Receptor do Peptídeo Semelhante ao Glucagon 1/agonistas , Receptor do Peptídeo Semelhante ao Glucagon 1/genética , Receptor do Peptídeo Semelhante ao Glucagon 1/metabolismo , Células HEK293 , Meia-Vida , Humanos , Hipoglicemiantes/sangue , Hipoglicemiantes/farmacocinética , Hipoglicemiantes/farmacologia , Incretinas/farmacologia , Incretinas/uso terapêutico , Liraglutida/farmacologia , Liraglutida/uso terapêutico , Masculino , Camundongos Endogâmicos C57BL , Camundongos Mutantes , Obesidade/sangue , Obesidade/metabolismo , Ratos Sprague-Dawley , Receptores dos Hormônios Gastrointestinais/genética , Receptores dos Hormônios Gastrointestinais/metabolismo , Receptores de Glucagon/genética , Receptores de Glucagon/metabolismo , Proteínas Recombinantes/química , Proteínas Recombinantes/genética , Proteínas Recombinantes/metabolismo , Redução de Peso/efeitos dos fármacos
4.
Bioorg Med Chem Lett ; 20(1): 26-30, 2010 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-19954978

RESUMO

A chemically diverse library of secondary and tertiary 4-cyanomethyl-1,5-diphenyl-1H-pyrazole-3-carboxamides was synthesized to enable mapping of the SAR, in the eastern amide region, with regard to CB1 antagonist activity, This study was initiated as a prelude to the design and synthesis of possible CB1 antagonists that do not readily pass the blood-brain-barrier. In general a range of modifications were found to be tolerated in this part of the molecule, although polar and especially charged groups did to a degree reduce the CB1 antagonistic activity. Several compounds with single-digit or even sub-nanomolar potency, suitable for further elaboration of the nitrile moiety, were identified.


Assuntos
Amidas/química , Receptor CB1 de Canabinoide/antagonistas & inibidores , Amidas/síntese química , Amidas/farmacologia , Barreira Hematoencefálica/metabolismo , Humanos , Receptor CB1 de Canabinoide/metabolismo , Bibliotecas de Moléculas Pequenas , Relação Estrutura-Atividade
5.
Bioorg Med Chem Lett ; 20(2): 453-7, 2010 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-20015647

RESUMO

A series of amides, amidines and amidoximes have been made from the corresponding nitrile compounds, to provide potent antagonists and inverse agonists for the CB1 receptor with considerably lower lipophiliciy, higher polar surface area and improved plasma/brain ratios compared to the centrally acting rimonabant. Extensive investigations of ADME and in vivo pharmacological properties led to selection of the amide series and specifically the 4-(4-fluorophenyl)piperidin-4-ol derivative D4. A clear improvement in the peripheral profile over rimonabant was seen, although some contribution of central effect on the pronounced weight reduction in obese mice cannot be ruled out.


Assuntos
Amidas/química , Fármacos Antiobesidade/química , Barreira Hematoencefálica/metabolismo , Piperidinas/química , Pirazóis/química , Receptor CB1 de Canabinoide/antagonistas & inibidores , Amidas/síntese química , Amidas/farmacologia , Animais , Fármacos Antiobesidade/síntese química , Fármacos Antiobesidade/farmacocinética , Peso Corporal , Agonismo Inverso de Drogas , Camundongos , Obesidade/tratamento farmacológico , Piperidinas/síntese química , Piperidinas/farmacologia , Ligação Proteica , Pirazóis/síntese química , Pirazóis/farmacologia , Ratos , Receptor CB1 de Canabinoide/metabolismo , Rimonabanto , Relação Estrutura-Atividade
6.
Bioorg Med Chem Lett ; 16(4): 1070-5, 2006 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-16289819

RESUMO

SAR explorations of the eastern and western parts of recently disclosed 2-aminoquinoline MCH1R-antagonists are reported. Eastern part investigations confirmed a high degree of structural freedom, and a number of additional single digit nanomolar antagonists were identified. Investigations of the western part also confirmed the initial SAR analysis, requiring a para-substituted phenyl ring spaced from the 6-amide by two connecting atoms. The exploration led to the discovery of a novel sub-series with a 4-biphenylcarboxamide western part, also exhibiting single digit nanomolar affinity.


Assuntos
Quinolinas/química , Quinolinas/farmacologia , Receptores de Somatostatina/antagonistas & inibidores , Estrutura Molecular , Quinolinas/síntese química , Estereoisomerismo , Relação Estrutura-Atividade
7.
J Med Chem ; 48(18): 5684-97, 2005 Sep 08.
Artigo em Inglês | MEDLINE | ID: mdl-16134937

RESUMO

Novel 6-acylamino-2-aminoquinoline melanin-concentrating hormone 1 receptor (MCH1R) antagonists were identified by sequential in silico screening with 3D pharmacophore models derived from a series of benzamide antagonists. The structure-activity relationship exploration by synthesis of analogues found structural demands around the western part of the compounds to be quite specific, whereas much structural freedom was found in the eastern part. While these compounds in general suffered from poor solubility properties, the 4-trifluoromethoxyphenoxyacetamide western appendage provided a favorable combination of activity and solubility properties. The amine in the eastern appendage, originally required by the pharmacophore model and believed to interact with Asp123 in transmembrane 3 of MCH1R, could be removed without diminishing affinity or functional activity of the compounds. Docking studies suggested that the Asp123 interacts preferentially with the nitrogen of the central quinoline. Synthesis and testing of specific analogues supported our revised binding mode hypothesis.


Assuntos
Aminoquinolinas/síntese química , Receptores de Somatostatina/antagonistas & inibidores , Aminoquinolinas/química , Aminoquinolinas/farmacologia , Animais , Sítios de Ligação , Células CHO , Cricetinae , Cricetulus , Humanos , Modelos Moleculares , Fosfatidilinositóis/metabolismo , Relação Quantitativa Estrutura-Atividade , Ensaio Radioligante , Receptores de Somatostatina/genética , Estereoisomerismo , Transfecção
8.
J Pharmacol Exp Ther ; 313(1): 78-87, 2005 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-15615862

RESUMO

Numerous studies have attested to the importance of the extreme C terminus of G protein alpha subunits in determining their selectivity of receptor recognition. We have previously reported that a highly conserved glycine residue within linker I is important for constraining the fidelity of receptor recognition by Galpha(q) proteins. Herein, we explored whether both modules (linker I and extreme C terminus) interact cooperatively in switching G protein-coupled receptor (GPCR)-to-effector specificity and created as models mutant Galpha(q) proteins in which glycine was replaced with various amino acids and the C-terminal five Galpha(q) residues with the corresponding Galpha(i) or Galpha(s) sequence. Coupling properties of the mutated Galpha(q) proteins were determined after coexpression with a panel of 13 G(i)-and G(s) -selective receptors and compared with those of Galpha proteins modified in only one module. Galpha proteins modified in both modules are significantly more efficacious in channeling non-G(q) -selective receptors to G(q)-mediated signaling events compare with those containing each module alone. Additive effects of both modules were observed even if individual modules lacked an effect on GPCR-to-effector specificity. Dually modified Galpha proteins were also superior in conferring high-affinity agonist sites onto a coexpressed GPCR in the absence, but not in the presence, of guanine nucleotides. Together, our data suggest that receptor-G protein coupling selectivity involves cooperative interactions between the extreme C terminus and linker I of Galpha proteins and that distinct determinants of selectivity exist for individual receptors.


Assuntos
Subunidades alfa de Proteínas de Ligação ao GTP/metabolismo , Glicina/metabolismo , Receptores Acoplados a Proteínas G/metabolismo , Sequência de Aminoácidos , Animais , Western Blotting , Células COS , Cálcio/metabolismo , Membrana Celular/metabolismo , Chlorocebus aethiops , Sequência Conservada , DNA/biossíntese , DNA/genética , Ensaio de Imunoadsorção Enzimática , Guanosina 5'-O-(3-Tiotrifosfato)/farmacologia , Fosfatos de Inositol/metabolismo , Ligantes , Dados de Sequência Molecular , Transdução de Sinais , Transfecção
9.
Bioorg Med Chem Lett ; 14(20): 5075-80, 2004 Oct 18.
Artigo em Inglês | MEDLINE | ID: mdl-15380202

RESUMO

Synthesis, in vitro biological evaluation and structure-activity relationships of 4-acylamino-and 4-ureidobenzamides as novel hMCH1R-antagonists are disclosed. The nature of the amine side chains could be varied considerably in contrast to the central benzamide scaffold and aromatic substituents.


Assuntos
Benzamidas/síntese química , Hormônios Hipotalâmicos/metabolismo , Melaninas/metabolismo , Hormônios Hipofisários/metabolismo , Receptores do Hormônio Hipofisário/antagonistas & inibidores , Ureia/análogos & derivados , Ureia/síntese química , Animais , Benzamidas/química , Benzamidas/farmacologia , Células CHO , Cricetinae , Cricetulus , Humanos , Ligantes , Ensaio Radioligante , Receptores do Hormônio Hipofisário/metabolismo , Relação Estrutura-Atividade , Ureia/química , Ureia/farmacologia
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