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1.
J Phycol ; 54(5): 703-719, 2018 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-30014469

RESUMO

Semiautomated methods for microscopic image acquisition, image analysis, and taxonomic identification have repeatedly received attention in diatom analysis. Less well studied is the question whether and how such methods might prove useful for clarifying the delimitation of species that are difficult to separate for human taxonomists. To try to answer this question, three very similar Fragilariopsis species endemic to the Southern Ocean were targeted in this study: F. obliquecostata, F. ritscheri, and F. sublinearis. A set of 501 extended focus depth specimen images were obtained using a standardized, semiautomated microscopic procedure. Twelve diatomists independently identified these specimen images in order to reconcile taxonomic opinions and agree upon a taxonomic gold standard. Using image analyses, we then extracted morphometric features representing taxonomic characters of the target taxa. The discriminating ability of individual morphometric features was tested visually and statistically, and multivariate classification experiments were performed to test the agreement of the quantitatively defined taxa assignments with expert consensus opinion. Beyond an updated differential diagnosis of the studied taxa, our study also shows that automated imaging and image analysis procedures for diatoms are coming close to reaching a broad applicability for routine use.

2.
J Med Chem ; 61(3): 681-694, 2018 Feb 08.
Artigo em Inglês | MEDLINE | ID: mdl-29316397

RESUMO

G protein-coupled receptor 40 (GPR40) has become an attractive target for the treatment of diabetes since it was shown clinically to promote glucose-stimulated insulin secretion. Herein, we report our efforts to develop highly selective and potent GPR40 agonists with a dual mechanism of action, promoting both glucose-dependent insulin and incretin secretion. Employing strategies to increase polarity and the ratio of sp3/sp2 character of the chemotype, we identified BMS-986118 (compound 4), which showed potent and selective GPR40 agonist activity in vitro. In vivo, compound 4 demonstrated insulinotropic efficacy and GLP-1 secretory effects resulting in improved glucose control in acute animal models.

3.
J Med Chem ; 60(4): 1417-1431, 2017 02 23.
Artigo em Inglês | MEDLINE | ID: mdl-28112924

RESUMO

A novel series of pyrrolidine-containing GPR40 agonists is described as a potential treatment for type 2 diabetes. The initial pyrrolidine hit was modified by moving the position of the carboxylic acid, a key pharmacophore for GPR40. Addition of a 4-cis-CF3 to the pyrrolidine improves the human GPR40 binding Ki and agonist efficacy. After further optimization, the discovery of a minor enantiomeric impurity with agonist activity led to the finding that enantiomers (R,R)-68 and (S,S)-68 have differential effects on the radioligand used for the binding assay, with (R,R)-68 potentiating the radioligand and (S,S)-68 displacing the radioligand. Compound (R,R)-68 activates both Gq-coupled intracellular Ca2+ flux and Gs-coupled cAMP accumulation. This signaling bias results in a dual mechanism of action for compound (R,R)-68, demonstrating glucose-dependent insulin and GLP-1 secretion in vitro. In vivo, compound (R,R)-68 significantly lowers plasma glucose levels in mice during an oral glucose challenge, encouraging further development of the series.


Assuntos
Hipoglicemiantes/farmacologia , Pirrolidinas/farmacologia , Receptores Acoplados a Proteínas-G/agonistas , Animais , Glicemia/análise , Glicemia/metabolismo , Linhagem Celular , Células Cultivadas , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/metabolismo , Peptídeo 1 Semelhante ao Glucagon/metabolismo , Humanos , Hipoglicemiantes/química , Hipoglicemiantes/farmacocinética , Hipoglicemiantes/uso terapêutico , Insulina/metabolismo , Masculino , Camundongos Endogâmicos C57BL , Modelos Moleculares , Pirrolidinas/química , Pirrolidinas/farmacocinética , Pirrolidinas/uso terapêutico , Ratos , Receptores Acoplados a Proteínas-G/metabolismo
4.
J Med Chem ; 59(19): 8848-8858, 2016 10 13.
Artigo em Inglês | MEDLINE | ID: mdl-27564419

RESUMO

The potent MCHR1 in vitro and in vivo antagonist activity of a series of cyclic tertiary alcohols derived from compound 2b is described. Subsequent pharmacokinetic and pharmacodynamic studies identified BMS-814580 (compound 10) as a highly efficacious antiobesity agent with a relatively clean in vitro and in vivo safety profile.


Assuntos
Fármacos Antiobesidade/química , Fármacos Antiobesidade/uso terapêutico , Obesidade/tratamento farmacológico , Pirimidinas/química , Pirimidinas/uso terapêutico , Receptores de Somatostatina/antagonistas & inibidores , Animais , Fármacos Antiobesidade/farmacocinética , Fármacos Antiobesidade/farmacologia , Cães , Halogenação , Humanos , Macaca fascicularis , Masculino , Camundongos , Pirimidinas/farmacocinética , Pirimidinas/farmacologia , Ratos , Receptores de Somatostatina/metabolismo , Relação Estrutura-Atividade
5.
ACS Med Chem Lett ; 7(6): 590-4, 2016 Jun 09.
Artigo em Inglês | MEDLINE | ID: mdl-27326332

RESUMO

BMS-711939 (3) is a potent and selective peroxisome proliferator-activated receptor (PPAR) α agonist, with an EC50 of 4 nM for human PPARα and >1000-fold selectivity vs human PPARγ (EC50 = 4.5 µM) and PPARδ (EC50 > 100 µM) in PPAR-GAL4 transactivation assays. Compound 3 also demonstrated excellent in vivo efficacy and safety profiles in preclinical studies and thus was chosen for further preclinical evaluation. The synthesis, structure-activity relationship (SAR) studies, and in vivo pharmacology of 3 in preclinical animal models as well as its ADME profile are described.

6.
Bioorg Med Chem Lett ; 25(14): 2793-9, 2015 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-26022839

RESUMO

Our investigation of the structure-activity and structure-liability relationships for dihydropyrrolopyrazol-6-one MCHR1 antagonists revealed that off-rate characteristics, inferred from potencies in a FLIPR assay following a 2 h incubation, can impact in vivo efficacy. The in vitro and exposure profiles of dihydropyrrolopyrazol-6-ones 1b and 1e were comparable to that of the thienopyrimidinone counterparts 41 and 43 except for a much faster MCHR1 apparent off-rate. The greatly diminished dihydropyrrolopyrazol-6-one anti-obesity response may be the consequence of this rapid off-rate.


Assuntos
Fármacos Antiobesidade/química , Pirazóis/química , Receptores de Somatostatina/antagonistas & inibidores , Animais , Fármacos Antiobesidade/farmacocinética , Fármacos Antiobesidade/farmacologia , Fármacos Antiobesidade/uso terapêutico , Meia-Vida , Humanos , Obesidade/tratamento farmacológico , Ligação Proteica , Pirazóis/farmacocinética , Pirazóis/farmacologia , Pirazóis/uso terapêutico , Ratos , Ratos Sprague-Dawley , Receptores de Somatostatina/metabolismo , Relação Estrutura-Atividade , Perda de Peso/efeitos dos fármacos
7.
J Med Chem ; 53(7): 2854-64, 2010 Apr 08.
Artigo em Inglês | MEDLINE | ID: mdl-20218621

RESUMO

An 1,3-oxybenzylglycine based compound 2 (BMS-687453) was discovered to be a potent and selective peroxisome proliferator activated receptor (PPAR) alpha agonist, with an EC(50) of 10 nM for human PPARalpha and approximately 410-fold selectivity vs human PPARgamma in PPAR-GAL4 transactivation assays. Similar potencies and selectivity were also observed in the full length receptor co-transfection assays. Compound 2 has negligible cross-reactivity against a panel of human nuclear hormone receptors including PPARdelta. Compound 2 demonstrated an excellent pharmacological and safety profile in preclinical studies and thus was chosen as a development candidate for the treatment of atherosclerosis and dyslipidemia. The X-ray cocrystal structures of the early lead compound 12 and compound 2 in complex with PPARalpha ligand binding domain (LBD) were determined. The role of the crystal structure of compound 12 with PPARalpha in the development of the SAR that ultimately resulted in the discovery of compound 2 is discussed.


Assuntos
Descoberta de Drogas , Glicina/análogos & derivados , Oxazóis/química , Oxazóis/farmacologia , PPAR alfa/agonistas , Animais , Linhagem Celular , Cricetinae , Cristalografia por Raios X , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos , Glicina/síntese química , Glicina/química , Glicina/farmacologia , Glicina/toxicidade , Humanos , Masculino , Camundongos , Modelos Moleculares , Oxazóis/síntese química , Oxazóis/toxicidade , PPAR alfa/química , PPAR alfa/genética , Estrutura Terciária de Proteína , Especificidade por Substrato , Ativação Transcricional/efeitos dos fármacos
8.
J Pharmacol Exp Ther ; 329(3): 1178-86, 2009 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-19252061

RESUMO

The orexigenic peptide ghrelin has been shown to have prokinetic activity in the gastrointestinal (GI) system of several species, including humans. In this series of experiments, we have evaluated the prokinetic activity of novel, small-molecule ghrelin receptor (GhrR) agonists after parenteral and peroral dosing in mice and rats. Gastric emptying, small intestinal transport, and fecal output were determined after intraperitoneal and intracerebroventricular dosing of GhrR agonists, using ghrelin as a positive control. These same parameters were evaluated after oral gavage dosing of the synthetic agonists. Regardless of dose route, GhrR agonist treatment increased gastric emptying, small intestinal transit, and fecal output. However, fecal output was only increased by GhrR agonist treatment if mice were able to feed during the stimulatory period. Thus, GhrR agonists can stimulate upper GI motility, and the orexigenic action of the compounds can indirectly contribute to prokinetic activity along the entire GI tract. The orexigenic and prokinetic effects of either ghrelin or small-molecule GhrR agonists were selective for the GhrR because they were absent when evaluated in GhrR knockout mice. We next evaluated the efficacy of the synthetic GhrR agonists dosed in a model of opiate-induced bowel dysfunction induced by a single injection of morphine. Oral dosing of a GhrR agonist normalized GI motility in opiate-induced dysmotility. These data demonstrate the potential utility of GhrR agonists for treating gastrointestinal hypomotility disorders.


Assuntos
Motilidade Gastrointestinal/efeitos dos fármacos , Grelina/administração & dosagem , Grelina/farmacologia , Hormônios Peptídicos/administração & dosagem , Hormônios Peptídicos/farmacologia , Receptores de Grelina/agonistas , Administração Oral , Animais , Peso Corporal/efeitos dos fármacos , Doença de Bowen/induzido quimicamente , Doença de Bowen/tratamento farmacológico , Doença de Bowen/fisiopatologia , Sistema Nervoso Central/efeitos dos fármacos , Defecação/efeitos dos fármacos , Ingestão de Alimentos/efeitos dos fármacos , Esvaziamento Gástrico/efeitos dos fármacos , Trânsito Gastrointestinal/efeitos dos fármacos , Intestino Delgado/efeitos dos fármacos , Intestino Delgado/fisiologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Morfina/farmacologia , Hormônios Peptídicos/sangue , Ratos , Ratos Sprague-Dawley , Receptores de Grelina/genética , Receptores de Grelina/metabolismo
9.
Bioorg Med Chem Lett ; 18(8): 2536-9, 2008 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-18378446

RESUMO

A novel series of N1 substituted tetrazole amides were prepared and showed to be potent growth hormone (GH) secretagogues. Among them, hydroxyl containing analog 31 displayed excellent in vivo activity by increasing plasma GH 10-fold in an anesthetized IV rat model.


Assuntos
Amidas/síntese química , Amidas/farmacologia , Hormônio do Crescimento/metabolismo , Tetrazóis/química , Amidas/química , Animais , Linhagem Celular , Glioma/metabolismo , Hormônio do Crescimento/sangue , Estrutura Molecular , Ratos , Relação Estrutura-Atividade
11.
J Med Chem ; 50(24): 5890-3, 2007 Nov 29.
Artigo em Inglês | MEDLINE | ID: mdl-17973363

RESUMO

A tetrazole-based peptidomimetic 2 (BMS-317180) was discovered as a human growth hormone secretagogue (GHS). Compound 2 is a potent, novel, orally effective GHS that shows an excellent safety profile in preclinical studies. The compound was advanced into clinical development.


Assuntos
Carbamatos/síntese química , Hormônio do Crescimento/metabolismo , Tetrazóis/síntese química , Administração Oral , Animais , Disponibilidade Biológica , Carbamatos/farmacocinética , Carbamatos/farmacologia , Cães , Ésteres , Hormônio do Crescimento/sangue , Hormônio do Crescimento Humano/metabolismo , Humanos , Macaca fascicularis , Ratos , Solubilidade , Relação Estrutura-Atividade , Tetrazóis/farmacocinética , Tetrazóis/farmacologia , Água
12.
Bioorg Med Chem Lett ; 17(21): 5928-33, 2007 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-17869100

RESUMO

A novel class of Growth Hormone Secretagogues (GHS), based on a tetrazole template, has been discovered. In vitro SAR and in vivo potency within this new class of GHS are described. The tetrazole 9q exhibits good oral bioavailability in rats and dogs as well as efficacy following an oral 10 mg/kg dose in dogs. Solution and solid phase protocols for the synthesis of tetrazole based GHS have been developed.


Assuntos
Hormônio do Crescimento/metabolismo , Tetrazóis/química , Tetrazóis/farmacologia , Animais , Cães , Relação Estrutura-Atividade , Tetrazóis/síntese química
13.
J Org Chem ; 62(10): 3153-3157, 1997 May 16.
Artigo em Inglês | MEDLINE | ID: mdl-11671698

RESUMO

The preparation and characterization of a homologous series of solid phase synthesis resins for anchoring amines via a Boc-like linker are described. The scope and limitations of these resins are explored with respect to procedures for attachment and cleavage of a variety of primary amines, secondary amines, and alpha-amino esters.

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