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1.
ACS Med Chem Lett ; 15(4): 424-431, 2024 Apr 11.
Artigo em Inglês | MEDLINE | ID: mdl-38628790

RESUMO

As we celebrate International Women's Day 2024 with the theme "Inspire Inclusion", the women of the ACS Medicinal Chemistry Division (MEDI) want to foster a sense of belonging, relevance, and empowerment by sharing uplifting stories of what inspired them to become medicinal chemists. In this editorial, we are featuring female medicinal chemistry scientists to provide role models, encouragement, and inspiration to others. We asked women medicinal chemists to contribute a brief paragraph about what inspired them to become medicinal chemists or what inspires them today as medicinal chemists. The responses and contributions highlight their passions and motivations, such as their love of the sciences and their drive to improve human health by contributing to basic research and creating lifesaving drugs.

2.
J Med Chem ; 67(6): 4251-4258, 2024 Mar 28.
Artigo em Inglês | MEDLINE | ID: mdl-38456628

RESUMO

As we celebrate International Women's Day 2024 with the theme "Inspire Inclusion", the women of the ACS Medicinal Chemistry Division (MEDI) want to foster a sense of belonging, relevance, and empowerment by sharing uplifting stories of what inspired them to become medicinal chemists. In this editorial, we are featuring female medicinal chemistry scientists to provide role models, encouragement, and inspiration to others. We asked women medicinal chemists to contribute a brief paragraph about what inspired them to become medicinal chemists or what inspires them today as medicinal chemists. The responses and contributions highlight their passions and motivations, such as their love of the sciences and their drive to improve human health by contributing to basic research and creating lifesaving drugs.


Assuntos
Química Farmacêutica , Poder Psicológico , Humanos , Feminino
3.
J Med Chem ; 65(24): 16234-16251, 2022 12 22.
Artigo em Inglês | MEDLINE | ID: mdl-36475645

RESUMO

With the emergence and rapid spreading of NDM-1 and existence of clinically relevant VIM-1 and IMP-1, discovery of pan inhibitors targeting metallo-beta-lactamases (MBLs) became critical in our battle against bacterial infection. Concurrent with our fragment and high-throughput screenings, we performed a knowledge-based search of known metallo-beta-lactamase inhibitors (MBLIs) to identify starting points for early engagement of medicinal chemistry. A class of compounds exemplified by 11, discovered earlier as B. fragilis metallo-beta-lactamase inhibitors, was selected for in silico virtual screening. From these efforts, compound 12 was identified with activity against NDM-1 only. Initial exploration on metal binding design followed by structure-guided optimization led to the discovery of a series of compounds represented by 23 with a pan MBL inhibition profile. In in vivo studies, compound 23 in combination with imipenem (IPM) robustly lowered the bacterial burden in a murine infection model and became the lead for the invention of MBLI clinical candidates.


Assuntos
Infecções Bacterianas , Inibidores de beta-Lactamases , Animais , Camundongos , Inibidores de beta-Lactamases/farmacologia , Inibidores de beta-Lactamases/uso terapêutico , Inibidores de beta-Lactamases/química , Imipenem/farmacologia , Imipenem/uso terapêutico , beta-Lactamases/metabolismo , Antibacterianos/farmacologia , Antibacterianos/uso terapêutico , Antibacterianos/química , Testes de Sensibilidade Microbiana
4.
J Med Chem ; 65(7): 5675-5689, 2022 04 14.
Artigo em Inglês | MEDLINE | ID: mdl-35332774

RESUMO

Stereochemically and structurally complex cyclic dinucleotide-based stimulator of interferon genes (STING) agonists were designed and synthesized to access a previously unexplored chemical space. The assessment of biochemical affinity and cellular potency, along with computational, structural, and biophysical characterization, was applied to influence the design and optimization of novel STING agonists, resulting in the discovery of MK-1454 as a molecule with appropriate properties for clinical development. When administered intratumorally to immune-competent mice-bearing syngeneic tumors, MK-1454 exhibited robust tumor cytokine upregulation and effective antitumor activity. Tumor shrinkage in mouse models that are intrinsically resistant to single-agent therapy was further enhanced when treating the animals with MK-1454 in combination with a fully murinized antimouse PD-1 antibody, mDX400. These data support the development of STING agonists in combination with pembrolizumab (humanized anti-PD-1 antibody) for patients with tumors that are partially responsive or nonresponsive to single-agent anti-PD-1 therapy.


Assuntos
Proteínas de Membrana , Neoplasias , Animais , Citocinas , Humanos , Imunoterapia/métodos , Interferons , Camundongos , Neoplasias/tratamento farmacológico
5.
J Med Chem ; 64(11): 7691-7701, 2021 06 10.
Artigo em Inglês | MEDLINE | ID: mdl-34038119

RESUMO

A renal outer medullary potassium channel (ROMK, Kir1.1) is a putative drug target for a novel class of diuretics with potential for treating hypertension and heart failure. Our first disclosed clinical ROMK compound, 2 (MK-7145), demonstrated robust diuresis, natriuresis, and blood pressure lowering in preclinical models, with reduced urinary potassium excretion compared to the standard of care diuretics. However, 2 projected to a short human half-life (∼5 h) that could necessitate more frequent than once a day dosing. In addition, a short half-life would confer a high peak-to-trough ratio which could evoke an excessive peak diuretic effect, a common liability associated with loop diuretics such as furosemide. This report describes the discovery of a new ROMK inhibitor 22e (MK-8153), with a longer projected human half-life (∼14 h), which should lead to a reduced peak-to-trough ratio, potentially extrapolating to more extended and better tolerated diuretic effects.


Assuntos
Natriuréticos/química , Bloqueadores dos Canais de Potássio/química , Canais de Potássio Corretores do Fluxo de Internalização/antagonistas & inibidores , Potenciais de Ação/efeitos dos fármacos , Animais , Benzofuranos/química , Pressão Sanguínea/efeitos dos fármacos , Diuréticos/química , Diuréticos/metabolismo , Diuréticos/farmacologia , Cães , Meia-Vida , Haplorrinos , Humanos , Masculino , Natriuréticos/metabolismo , Natriuréticos/farmacologia , Piperazinas/química , Potássio/urina , Bloqueadores dos Canais de Potássio/metabolismo , Bloqueadores dos Canais de Potássio/farmacologia , Canais de Potássio Corretores do Fluxo de Internalização/metabolismo , Ratos , Ratos Endogâmicos SHR
6.
Bioorg Med Chem Lett ; 30(21): 127574, 2020 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-32980512

RESUMO

The NO-sGC-cGMP signaling pathway plays an important role in the cardiovascular system. Loss of nitric oxide tone or impaired signaling has been associated with cardiovascular diseases, such as hypertension, pulmonary hypertension and heart failure. Direct activation of sGC enzyme independent of NO represents a novel approach for modulating NO signaling with tremendous therapeutic potential. Herein, we describe the design of a structurally novel class of heme-dependent sGC stimulators containing the 3,3-dimethylpyrrolidin-2-one moiety which resulted in the identification of the potent, selective stimulator 30 (MK-2947) for the treatment of hypertension.


Assuntos
Anti-Hipertensivos/farmacologia , Descoberta de Drogas , Hipertensão/tratamento farmacológico , Guanilil Ciclase Solúvel/metabolismo , Anti-Hipertensivos/química , Relação Dose-Resposta a Droga , Humanos , Estrutura Molecular , Relação Estrutura-Atividade
7.
Science ; 363(6424)2019 Jan 18.
Artigo em Inglês | MEDLINE | ID: mdl-30655413

RESUMO

Innovations in synthetic chemistry have enabled the discovery of many breakthrough therapies that have improved human health over the past century. In the face of increasing challenges in the pharmaceutical sector, continued innovation in chemistry is required to drive the discovery of the next wave of medicines. Novel synthetic methods not only unlock access to previously unattainable chemical matter, but also inspire new concepts as to how we design and build chemical matter. We identify some of the most important recent advances in synthetic chemistry as well as opportunities at the interface with partner disciplines that are poised to transform the practice of drug discovery and development.


Assuntos
Química Farmacêutica/tendências , Descoberta de Drogas , Preparações Farmacêuticas/síntese química , Biocatálise , Indústria Farmacêutica , Enzimas/química , Ensaios de Triagem em Larga Escala , Invenções , Aprendizado de Máquina , Fotoquímica
8.
J Med Chem ; 60(9): 3851-3865, 2017 05 11.
Artigo em Inglês | MEDLINE | ID: mdl-28322556

RESUMO

We describe our optimization efforts to improve the physicochemical properties, solubility, and off-target profile of 1, an inhibitor of TarO, an early stage enzyme in the biosynthetic pathway for wall teichoic acid (WTA) synthesis. Compound 1 displayed a TarO IC50 of 125 nM in an enzyme assay and possessed very high lipophilicity (clogP = 7.1) with no measurable solubility in PBS buffer. Structure-activity relationship (SAR) studies resulted in a series of compounds with improved lipophilic ligand efficiency (LLE) consistent with the reduction of clogP. From these efforts, analog 9 was selected for our initial in vivo study, which in combination with subefficacious dose of imipenem (IPM) robustly lowered the bacterial burden in a neutropenic Staphylococci murine infection model. Concurrent with our in vivo optimization effort using 9, we further improved LLE as exemplified by a much more druglike analog 26.


Assuntos
Lipídeos/química , Bibliotecas de Moléculas Pequenas , Animais , Feminino , Staphylococcus aureus Resistente à Meticilina/efeitos dos fármacos , Staphylococcus aureus Resistente à Meticilina/crescimento & desenvolvimento , Camundongos , Camundongos Endogâmicos BALB C , Testes de Sensibilidade Microbiana , Solubilidade , Relação Estrutura-Atividade
9.
Bioorg Med Chem Lett ; 27(9): 2069-2073, 2017 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-28284804

RESUMO

Glucokinase (GK, hexokinase IV) is a unique hexokinase that plays a central role in mammalian glucose homeostasis. Glucose phosphorylation by GK in the pancreatic ß-cell is the rate-limiting step that controls glucose-stimulated insulin secretion. Similarly, GK-mediated glucose phosphorylation in hepatocytes plays a major role in increasing hepatic glucose uptake and metabolism and possibly lowering hepatic glucose output. Small molecule GK activators (GKAs) have been identified that increase enzyme activity by binding to an allosteric site. GKAs offer a novel approach for the treatment of Type 2 Diabetes Mellitus (T2DM) and as such have garnered much attention. We now report the design, synthesis, and biological evaluation of a novel series of 2,5,6-trisubstituted indole derivatives that act as highly potent GKAs. Among them, Compound 1 was found to possess high in vitro potency, excellent physicochemical properties, and good pharmacokinetic profile in rodents. Oral administration of Compound 1 at doses as low as 0.03mg/kg led to robust blood glucose lowering efficacy in 3week high fat diet-fed mice.


Assuntos
Diabetes Mellitus Tipo 2/tratamento farmacológico , Ativadores de Enzimas/química , Ativadores de Enzimas/uso terapêutico , Glucoquinase/metabolismo , Hipoglicemiantes/química , Hipoglicemiantes/uso terapêutico , Indóis/química , Indóis/uso terapêutico , Regulação Alostérica/efeitos dos fármacos , Animais , Glicemia/análise , Glicemia/metabolismo , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/metabolismo , Desenho de Fármacos , Ativação Enzimática/efeitos dos fármacos , Ativadores de Enzimas/farmacocinética , Ativadores de Enzimas/farmacologia , Humanos , Hipoglicemiantes/farmacocinética , Hipoglicemiantes/farmacologia , Indóis/farmacocinética , Indóis/farmacologia , Insulina/sangue , Insulina/metabolismo , Camundongos , Camundongos Endogâmicos C57BL
10.
Bioorg Med Chem Lett ; 27(9): 2063-2068, 2017 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-28284809

RESUMO

Systemically acting glucokinase activators (GKA) have been demonstrated in clinical trials to effectively lower blood glucose in patients with type II diabetes. However, mechanism-based hypoglycemia is a major adverse effect that limits the therapeutic potential of these agents. We hypothesized that the predominant mechanism leading to hypoglycemia is GKA-induced excessive insulin secretion from pancreatic ß-cells at (sub-)euglycemic levels. We further hypothesized that restricting GK activation to hepatocytes would maintain glucose-lowering efficacy while significantly reducing hypoglycemic risk. Here we report the discovery of a novel series of carboxylic acid substituted GKAs based on pyridine-2-carboxamide. These GKAs exhibit preferential distribution to the liver versus the pancreas in mice. SAR studies led to the identification of a potent and orally active hepatoselective GKA, compound 6. GKA 6 demonstrated robust glucose lowering efficacy in high fat diet-fed mice at doses ⩾10mpk, with ⩾70-fold liver:pancreas distribution, minimal effects on plasma insulin levels, and significantly reduced risk of hypoglycemia.


Assuntos
Diabetes Mellitus Tipo 2/tratamento farmacológico , Ativadores de Enzimas/farmacologia , Glucoquinase/metabolismo , Hipoglicemiantes/farmacologia , Piridinas/farmacologia , Animais , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/metabolismo , Descoberta de Drogas , Ativadores de Enzimas/química , Ativadores de Enzimas/farmacocinética , Ativadores de Enzimas/uso terapêutico , Humanos , Hipoglicemiantes/química , Hipoglicemiantes/farmacocinética , Hipoglicemiantes/uso terapêutico , Insulina/sangue , Fígado/efeitos dos fármacos , Fígado/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Pâncreas/efeitos dos fármacos , Pâncreas/metabolismo , Piridinas/química , Piridinas/farmacocinética , Piridinas/uso terapêutico
11.
Bioorg Med Chem Lett ; 26(23): 5695-5702, 2016 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-27839686

RESUMO

Following the discovery of small molecule acyl piperazine ROMK inhibitors, the acyl octahydropyrazino[2,1-c][1,4]oxazine series was identified. This series displays improved ROMK/hERG selectivity, and as a consequence, the resulting ROMK inhibitors do not evoke QTc prolongation in an in vivo cardiovascular dog model. Further efforts in this series led to the discovery of analogs with improved pharmacokinetic profiles. This new series also retained comparable ROMK potency compared to earlier leads.


Assuntos
Oxazinas/química , Oxazinas/farmacologia , Canais de Potássio Corretores do Fluxo de Internalização/antagonistas & inibidores , Animais , Diurese/efeitos dos fármacos , Cães , Insuficiência Cardíaca/tratamento farmacológico , Humanos , Hipertensão/tratamento farmacológico , Macaca mulatta , Oxazinas/farmacocinética , Canais de Potássio Corretores do Fluxo de Internalização/metabolismo , Ratos Sprague-Dawley , Regulador Transcricional ERG/antagonistas & inibidores , Regulador Transcricional ERG/metabolismo
12.
ACS Med Chem Lett ; 7(7): 697-701, 2016 Jul 14.
Artigo em Inglês | MEDLINE | ID: mdl-27437080

RESUMO

ROMK, the renal outer medullary potassium channel, is involved in potassium recycling at the thick ascending loop of Henle and potassium secretion at the cortical collecting duct in the kidney nephron. Because of this dual site of action, selective inhibitors of ROMK are expected to represent a new class of diuretics/natriuretics with superior efficacy and reduced urinary loss of potassium compared to standard-of-care loop and thiazide diuretics. Following our earlier work, this communication will detail subsequent medicinal chemistry endeavors to further improve lead selectivity against the hERG channel and preclinical pharmacokinetic properties. Pharmacological assessment of highlighted inhibitors will be described, including pharmacodynamic studies in both an acute rat diuresis/natriuresis model and a subchronic blood pressure model in spontaneous hypertensive rats. These proof-of-biology studies established for the first time that the human and rodent genetics accurately predict the in vivo pharmacology of ROMK inhibitors and supported identification of the first small molecule ROMK inhibitor clinical candidate, MK-7145.

13.
Cell Chem Biol ; 23(1): 10-17, 2016 Jan 21.
Artigo em Inglês | MEDLINE | ID: mdl-26933732

RESUMO

Chemical probes represent an important component of both academic and pharmaceutical drug discovery research. As a complement to prior reviews that have defined this scientific field, we aim to provide an industry perspective on the value of having high-quality chemical probes throughout the course of preclinical research. By studying examples from the internal Merck pipeline, we recognize that these probes require significant collaborative investment to realize their potential impact in clarifying the tractability and translation of a given therapeutic target. This perspective concludes with recommendations for chemical probe discovery aimed toward maximizing their potential to identify targets that result in the successful delivery of novel therapeutics.


Assuntos
Descoberta de Drogas/métodos , Proteínas/metabolismo , Bibliotecas de Moléculas Pequenas/química , Bibliotecas de Moléculas Pequenas/farmacologia , Animais , Dipeptidil Peptidase 4/metabolismo , Inibidores da Dipeptidil Peptidase IV/química , Inibidores da Dipeptidil Peptidase IV/farmacologia , Inibidores de Integrase de HIV/química , Inibidores de Integrase de HIV/farmacologia , Humanos , Serina-Treonina Proteína Quinase-2 com Repetições Ricas em Leucina , Terapia de Alvo Molecular , Biossíntese de Proteínas/efeitos dos fármacos , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Proteínas Serina-Treonina Quinases/metabolismo , Proteínas/agonistas , Proteínas/antagonistas & inibidores , Proteínas Proto-Oncogênicas c-akt/antagonistas & inibidores , Proteínas Proto-Oncogênicas c-akt/metabolismo , Receptor CB2 de Canabinoide/agonistas , Receptor CB2 de Canabinoide/metabolismo
14.
Bioorg Med Chem Lett ; 25(19): 4143-7, 2015 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-26303893

RESUMO

A novel, potent series of glucagon receptor antagonists (GRAs) was discovered. These indazole- and indole-based compounds were designed on an earlier pyrazole-based GRA lead MK-0893. Structure-activity relationship (SAR) studies were focused on the C3 and C6 positions of the indazole core, as well as the benzylic position on the N-1 of indazole. Multiple potent GRAs were identified with excellent in vitro profiles and good pharmacokinetics in rat. Among them, GRA 16d was found to be orally active in blunting glucagon induced glucose excursion in an acute glucagon challenge model in glucagon receptor humanized (hGCGR) mice at 1, 3 and 10mg/kg (mpk), and significantly lowered acute glucose levels in hGCGR ob/ob mice at 3 mpk dose.


Assuntos
Indazóis/química , Indazóis/farmacologia , Indóis/química , Indóis/farmacologia , Receptores de Glucagon/antagonistas & inibidores , Animais , Células CHO , Cricetulus , Relação Dose-Resposta a Droga , Humanos , Camundongos , Camundongos Obesos , Estrutura Molecular , Ratos , Relação Estrutura-Atividade
15.
ACS Med Chem Lett ; 6(7): 747-52, 2015 Jul 09.
Artigo em Inglês | MEDLINE | ID: mdl-26191360

RESUMO

A new subseries of ROMK inhibitors exemplified by 28 has been developed from the initial screening hit 1. The excellent selectivity for ROMK inhibition over related ion channels and pharmacokinetic properties across preclinical species support further preclinical evaluation of 28 as a new mechanism diuretic. Robust pharmacodynamic effects in both SD rats and dogs have been demonstrated.

16.
PLoS One ; 7(11): e49572, 2012.
Artigo em Inglês | MEDLINE | ID: mdl-23185367

RESUMO

Hyperglucagonemia is implicated in the pathophysiology of hyperglycemia. Antagonism of the glucagon receptor (GCGR) thus represents a potential approach to diabetes treatment. Herein we report the characterization of GRA1, a novel small-molecule GCGR antagonist that blocks glucagon binding to the human GCGR (hGCGR) and antagonizes glucagon-induced intracellular accumulation of cAMP with nanomolar potency. GRA1 inhibited glycogenolysis dose-dependently in primary human hepatocytes and in perfused liver from hGCGR mice, a transgenic line of mouse that expresses the hGCGR instead of the murine GCGR. When administered orally to hGCGR mice and rhesus monkeys, GRA1 blocked hyperglycemic responses to exogenous glucagon. In several murine models of diabetes, acute and chronic dosing with GRA1 significantly reduced blood glucose concentrations and moderately increased plasma glucagon and glucagon-like peptide-1. Combination of GRA1 with a dipeptidyl peptidase-4 inhibitor had an additive antihyperglycemic effect in diabetic mice. Hepatic gene-expression profiling in monkeys treated with GRA1 revealed down-regulation of numerous genes involved in amino acid catabolism, an effect that was paralleled by increased amino acid levels in the circulation. In summary, GRA1 is a potent glucagon receptor antagonist with strong antihyperglycemic efficacy in preclinical models and prominent effects on hepatic gene-expression related to amino acid metabolism.


Assuntos
Regulação da Expressão Gênica , Hipoglicemiantes/farmacologia , Pirazóis/farmacologia , Receptores de Glucagon/antagonistas & inibidores , beta-Alanina/análogos & derivados , Administração Oral , Animais , Relação Dose-Resposta a Droga , Perfilação da Expressão Gênica , Glucagon/sangue , Glucagon/química , Glicogênio/metabolismo , Glicogenólise , Hepatócitos/efeitos dos fármacos , Hormônios/sangue , Humanos , Radioisótopos do Iodo/química , Fígado/metabolismo , Macaca mulatta , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Modelos Químicos , beta-Alanina/farmacologia
17.
J Med Chem ; 55(13): 6137-48, 2012 Jul 12.
Artigo em Inglês | MEDLINE | ID: mdl-22708876

RESUMO

A potent, selective glucagon receptor antagonist 9m, N-[(4-{(1S)-1-[3-(3,5-dichlorophenyl)-5-(6-methoxynaphthalen-2-yl)-1H-pyrazol-1-yl]ethyl}phenyl)carbonyl]-ß-alanine, was discovered by optimization of a previously identified lead. Compound 9m is a reversible and competitive antagonist with high binding affinity (IC(50) of 6.6 nM) and functional cAMP activity (IC(50) of 15.7 nM). It is selective for glucagon receptor relative to other family B GPCRs, showing IC(50) values of 1020 nM for GIPR, 9200 nM for PAC1, and >10000 nM for GLP-1R, VPAC1, and VPAC2. Compound 9m blunted glucagon-induced glucose elevation in hGCGR mice and rhesus monkeys. It also lowered ambient glucose levels in both acute and chronic mouse models: in hGCGR ob/ob mice it reduced glucose (AUC 0-6 h) by 32% and 39% at 3 and 10 mpk single doses, respectively. In hGCGR mice on a high fat diet, compound 9m at 3, and 10 mpk po in feed lowered blood glucose levels by 89% and 94% at day 10, respectively, relative to the difference between the vehicle control and lean hGCGR mice. On the basis of its favorable biological and DMPK properties, compound 9m (MK-0893) was selected for further preclinical and clinical evaluations.


Assuntos
Glicemia/metabolismo , Diabetes Mellitus Tipo 2/tratamento farmacológico , Glucagon/metabolismo , Pirazóis/farmacologia , Receptores de Glucagon/antagonistas & inibidores , beta-Alanina/análogos & derivados , Animais , Área Sob a Curva , Células CHO , Cricetinae , Cricetulus , Dieta Hiperlipídica/efeitos adversos , Modelos Animais de Doenças , Cães , Receptor do Peptídeo Semelhante ao Glucagon 1 , Humanos , Concentração Inibidora 50 , Macaca mulatta , Camundongos , Camundongos Obesos , Microssomos Hepáticos/metabolismo , Pirazóis/química , Pirazóis/uso terapêutico , Ratos , Receptores dos Hormônios Gastrointestinais/antagonistas & inibidores , Receptores de Polipeptídeo Hipofisário Ativador de Adenilato Ciclase/antagonistas & inibidores , Receptores Tipo II de Peptídeo Intestinal Vasoativo/antagonistas & inibidores , Receptores Tipo I de Polipeptídeo Intestinal Vasoativo/antagonistas & inibidores , beta-Alanina/química , beta-Alanina/farmacologia , beta-Alanina/uso terapêutico
18.
Bioorg Med Chem Lett ; 21(23): 7124-30, 2011 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-22030028

RESUMO

A novel class of N-aryl-2-acylindole human glucagon receptor (hGCGR) antagonists is reported. These compounds demonstrate good pharmacokinetic profiles in multiple preclinical species. One compound from this series, indole 33, is orally active in a transgenic murine pharmacodynamic model. Furthermore, a 1mg/kg oral dose of indole 33 lowers ambient glucose levels in an ob/ob/hGCGR transgenic murine diabetes model. This compound was deemed suitable for preclinical safety studies and was found to be well tolerated in an 8-day experimental rodent tolerability study. The combination of preclinical efficacy and safety observed with compound 33 highlights the potential of this class as a treatment for type 2 diabetes.


Assuntos
Glicemia/efeitos dos fármacos , Descoberta de Drogas , Hipoglicemiantes , Indóis/síntese química , Indóis/farmacologia , Receptores de Glucagon/antagonistas & inibidores , Administração Oral , Animais , Diabetes Mellitus Tipo 2/tratamento farmacológico , Cães , Humanos , Hipoglicemiantes/síntese química , Hipoglicemiantes/química , Hipoglicemiantes/farmacologia , Indóis/química , Camundongos , Camundongos Transgênicos , Estrutura Molecular , Relação Estrutura-Atividade
19.
Bioorg Med Chem Lett ; 21(23): 7131-6, 2011 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-22001094

RESUMO

In the course of the development of an aminobenzimidazole class of human glucagon receptor (hGCGR) antagonists, a novel class of cyclic guanidine hGCGR antagonists was discovered. Rapid N-dealkylation resulted in poor pharmacokinetic profiles for the benchmark compound in this series. A strategy aimed at blocking oxidative dealkylation led to a series of compounds with improved rodent pharmacokinetic profiles. One compound was orally efficacious in a murine glucagon challenge pharmacodynamic model and also significantly lowered glucose levels in a murine diabetes model.


Assuntos
Glicemia/efeitos dos fármacos , Descoberta de Drogas , Guanidinas/síntese química , Receptores de Glucagon/antagonistas & inibidores , Administração Oral , Animais , Ciclização , Diabetes Mellitus Tipo 2/tratamento farmacológico , Modelos Animais de Doenças , Cães , Guanidinas/química , Guanidinas/farmacologia , Humanos , Hipoglicemiantes/síntese química , Hipoglicemiantes/química , Hipoglicemiantes/farmacologia , Concentração Inibidora 50 , Estrutura Molecular , Ratos , Relação Estrutura-Atividade
20.
Expert Opin Ther Pat ; 21(8): 1211-40, 2011 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-21635155

RESUMO

INTRODUCTION: The ever increasing prevalence of type 2 diabetes mellitus (T2DM) in the developed and developing nations calls for the introduction of new and more effective treatments. Glucagon receptor (GCGR) antagonists are highly validated in preclinical models of T2DM and thus have the potential to be developed as a new therapy. Small molecule GCGR antagonists have been an active area of research since the 1990s. As evidenced from the number of patents and laboratories involved, these efforts have accelerated during the last decade. AREAS COVERED: During the period 2006 - 2010, there were numerous patent publications from several laboratories claiming the discovery of novel small molecule GCGR antagonists. Herein, we present our interpretation of these new patent publications as well as follow-up disclosures appearing in the peer-reviewed literature. This paper provides an up-to-date overview of the field of small molecule GCGR antagonism as a potential treatment for T2DM. Attempts were made wherever possible to identify preferred or representative compounds from the patent applications reviewed. In vitro and in vivo data are also discussed where they were disclosed. EXPERT OPINION: The novel small molecule GCGR antagonists reviewed here represent many diverse structural motifs. Some molecules are very potent antagonists of the GCGR in in vitro assays with acceptable selectivity. Some have intriguing in vivo activity in models of T2DM in a variety of preclinical species. It is to be hoped that clinical developments following these preclinical discoveries might result in a long-awaited new treatment for T2DM.


Assuntos
Diabetes Mellitus Tipo 2/tratamento farmacológico , Hipoglicemiantes/farmacologia , Patentes como Assunto , Receptores de Glucagon/antagonistas & inibidores , Animais , Diabetes Mellitus Tipo 2/metabolismo , Humanos , Hipoglicemiantes/química , Receptores de Glucagon/metabolismo , Relação Estrutura-Atividade
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