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1.
Pituitary ; 25(2): 328-339, 2022 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-35000098

RESUMO

PURPOSE: Evaluate the pharmacodynamics, pharmacokinetics, and safety of paltusotine, an orally bioavailable, nonpeptide, somatostatin receptor subtype 2 (SST2) agonist being developed for the treatment of acromegaly and neuroendocrine tumors. METHODS: A randomized, double-blind, placebo-controlled, single center, single and multiple ascending dose phase 1 study was conducted in healthy male volunteers who received (i) single-dose of oral paltusotine 1.25, 2.5, 5, 10, and 20 mg (solution); and 40 and 60 mg (capsules) or (ii) multiple-dose oral paltusotine capsules once daily 5 mg (× 7 days), 10, 20, and 30 mg (× 10 days). Main outcome measures were pharmacodynamics (changes in growth hormone-releasing hormone [GHRH] stimulated growth hormone [GH] and insulin-like growth factor 1 [IGF-1]), pharmacokinetics, safety, and tolerability. RESULTS: Single-dose cohorts: n = 41 active, n = 14 placebo. Multiple-dose cohorts: n = 24 active, n = 12 placebo. Paltusotine was well tolerated, orally bioavailable, associated with increased plasma concentrations to doses up to 40 mg, and was eliminated with a half-life of approximately 30 h. Single-dose paltusotine 1.25 to 20 mg suppressed GHRH-stimulated GH secretion by 44% to 93% compared to 15% with placebo. Multiple-dose paltusotine 5 to 30 mg administered once daily for 10 days suppressed IGF-1 by 19% to 37% compared to an increase of 2.4% with placebo. CONCLUSIONS: Paltusotine suppresses GH and IGF-1 in a dose-dependent fashion, with a safety profile similar to currently approved SST2 receptor ligands. Paltusotine is a promising once-daily oral nonpeptide SST2 agonist candidate for managing acromegaly and neuroendocrine tumors. TRIAL REGISTRATION: NCT03276858, registered September 8, 2017, retrospectively registered.


Assuntos
Acromegalia , Hormônio do Crescimento Humano , Acromegalia/tratamento farmacológico , Método Duplo-Cego , Hormônio do Crescimento/metabolismo , Voluntários Saudáveis , Hormônio do Crescimento Humano/metabolismo , Humanos , Fator de Crescimento Insulin-Like I/metabolismo , Masculino
2.
J Pharmacol Exp Ther ; 361(3): 454-461, 2017 06.
Artigo em Inglês | MEDLINE | ID: mdl-28404690

RESUMO

The vesicular monoamine transporter 2 (VMAT2) is an integral presynaptic protein that regulates the packaging and subsequent release of dopamine and other monoamines from neuronal vesicles into the synapse. Valbenazine (NBI-98854), a novel compound that selectively inhibits VMAT2, is approved for the treatment of tardive dyskinesia. Valbenazine is converted to two significant circulating metabolites in vivo, namely, (+)-α-dihydrotetrabenazine (R,R,R-HTBZ) and a mono-oxy metabolite, NBI-136110. Radioligand-binding studies were conducted to assess and compare valbenazine, tetrabenazine, and their respective metabolites in their abilities to selectively and potently inhibit [3H]-HTBZ binding to VMAT2 in rat striatal, rat forebrain, and human platelet homogenates. A broad panel screen was conducted to evaluate possible off-target interactions of valbenazine, R,R,R-HTBZ, and NBI-136110 at >80 receptor, transporter, and ion channel sites. Radioligand binding showed R,R,R-HTBZ to be a potent VMAT2 inhibitor in homogenates of rat striatum (Ki = 1.0-2.8 nM), rat forebrain (Ki = 4.2 nM), and human platelets (Ki = 2.6-3.3 nM). Valbenazine (Ki = 110-190 nM) and NBI-136110 (Ki = 160-220 nM) also exhibited inhibitory effects on VMAT2, but with lower potency than R,R,R-HTBZ. Neither valbenazine, R,R,R-HTBZ, nor NBI-136110 had significant off-target interactions at serotonin (5-HT1A, 5-HT2A, 5-HT2B) or dopamine (D1 or D2) receptor sites. In vivo studies measuring ptosis and prolactin secretion in the rat confirmed the specific and dose-dependent interactions of tetrabenazine and R,R,R-HTBZ with VMAT2. Evaluations of potency and selectivity of tetrabenazine and its pharmacologically active metabolites were also performed. Overall, the pharmacologic characteristics of valbenazine appear consistent with the favorable efficacy and tolerability findings of recent clinical studies [KINECT 2 (NCT01733121), KINECT 3 (NCT02274558)].


Assuntos
Tetrabenazina/análogos & derivados , Valina/análogos & derivados , Proteínas Vesiculares de Transporte de Monoamina/antagonistas & inibidores , Proteínas Vesiculares de Transporte de Monoamina/metabolismo , Animais , Plaquetas/efeitos dos fármacos , Plaquetas/metabolismo , Células CHO , Corpo Estriado/efeitos dos fármacos , Corpo Estriado/metabolismo , Cricetinae , Cricetulus , Células HEK293 , Humanos , Ligação Proteica/efeitos dos fármacos , Ligação Proteica/fisiologia , Ratos , Tetrabenazina/metabolismo , Tetrabenazina/farmacologia , Valina/metabolismo , Valina/farmacologia
3.
J Clin Endocrinol Metab ; 108(5): e148-e159, 2023 04 13.
Artigo em Inglês | MEDLINE | ID: mdl-36353760

RESUMO

CONTEXT: Paltusotine is a once-daily, oral, nonpeptide small-molecule somatostatin receptor type 2 (SST2) agonist in clinical development for treatment of acromegaly. OBJECTIVE: This work aimed to evaluate change in insulin-like growth factor I (IGF-I) levels in patients switched from octreotide long-acting release or lanreotide depot monotherapy to paltusotine. METHODS: A phase 2, open-label, prospective, multicenter, multinational, nonrandomized, single-arm exploratory study was conducted in which dosage uptitrations were performed in a double-blinded manner. At 26 global sites, patients with acromegaly switched to paltusotine from injected somatostatin receptor ligand (SRL)-based therapy. Patients received 13-week treatment with once-daily oral paltusotine (10-40 mg/d). The primary end point was change from baseline to week 13 in IGF-I for patients who switched from long-acting octreotide or lanreotide depot monotherapy to paltusotine (group 1). All patients underwent a 4-week paltusotine washout at end of treatment period (wk 13-17). IGF-I, growth hormone (GH), patient-reported outcome, and safety data were collected. RESULTS: Forty-seven patients enrolled. In group 1 (n = 25), IGF-I and GH showed no significant change between SRL baseline and end of paltusotine treatment at week 13 (median change in IGF-I = -0.03×upper limit of normal [ULN]; P = .6285; GH = -0.05 ng/mL; P = .6285). IGF-I and GH rose significantly in the 4 weeks after withdrawing paltusotine (median change in IGF-I = 0.55×ULN; P < .0001 [median increase 39%]; GH = 0.72 ng/mL; P < .0001 [109.1% increase]). No patients discontinued because of adverse events (AE); no treatment-related serious AEs were reported. CONCLUSION: These results suggest once-daily oral paltusotine was effective in maintaining IGF-I values in patients with acromegaly who switched from injected SRLs. Paltusotine was well tolerated with a safety profile consistent with other SRLs.


Assuntos
Acromegalia , Hormônio do Crescimento Humano , Humanos , Acromegalia/tratamento farmacológico , Acromegalia/metabolismo , Octreotida/uso terapêutico , Fator de Crescimento Insulin-Like I/metabolismo , Estudos Prospectivos , Peptídeos Cíclicos/efeitos adversos , Resultado do Tratamento
4.
ACS Med Chem Lett ; 14(1): 66-74, 2023 Jan 12.
Artigo em Inglês | MEDLINE | ID: mdl-36655128

RESUMO

The discovery of a novel 4-(4-aminopiperidinyl)-3,6-diarylquinoline series of potent SST2 agonists is described. This class of molecules exhibit excellent selectivity over SST1, SST3, SST4, and SST5 receptors. The compound 3-[4-(4-aminopiperidin-1-yl)-3-(3,5-difluorophenyl)quinolin-6-yl]-2-hydroxybenzonitrile (22, paltusotine, formerly known as CRN00808) showed no direct inhibition of major cytochrome P450 enzymes or the hERG ion channel and had sufficient exposure in rats and excellent exposure in dogs upon oral dosing. In pharmacodynamic studies, compound 22 dose-dependently suppressed growth hormone (GH) secretion induced by an exogenous growth-hormone-releasing hormone (GHRH) challenge in both male and female rats following a single oral dose and suppressed IGF-1 levels with repeated oral administration in both rats and dogs. To the best of our knowledge, compound 22 is the first non-peptide SST2 agonist to advance to human clinical trials and is currently in Phase 3 trials in acromegaly patients and a Phase 2 trial in neuroendocrine tumor patients suffering from carcinoid syndrome.

5.
Bioorg Med Chem Lett ; 22(1): 421-6, 2012 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-22153347

RESUMO

The structure-activity relationships of 2-(piperidin-3-yl)-1H-benzimidazoles, 2-morpholine and 2-thiomorpholin-2-yl-1H-benzimidazoles are described. In the lead optimization process, the pK(a) and/or logP of benzimidazole analogs were reduced either by attachment of polar substituents to the piperidine nitrogen or incorporation of heteroatoms into the piperidine heterocycle. Compounds 9a and 9b in the morpholine series and 10g in the thiomorpholine series demonstrated improved selectivity and CNS profiles compared to lead compound 2 and these are potential candidates for evaluation as sedative hypnotics.


Assuntos
Benzimidazóis/síntese química , Antagonistas dos Receptores Histamínicos H1/farmacologia , Distúrbios do Início e da Manutenção do Sono/tratamento farmacológico , Benzimidazóis/farmacologia , Sistema Nervoso Central/efeitos dos fármacos , Desenho de Fármacos , Canal de Potássio ERG1 , Eletrofisiologia/métodos , Canais de Potássio Éter-A-Go-Go/química , Humanos , Hipnóticos e Sedativos/farmacologia , Concentração Inibidora 50 , Cinética , Microssomos Hepáticos/efeitos dos fármacos , Modelos Químicos , Morfolinas/química , Nitrogênio/química , Piperidinas/química , Receptores Histamínicos H1/química , Relação Estrutura-Atividade
6.
J Oral Maxillofac Pathol ; 26(4): 555-557, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-37082045

RESUMO

The world today is in the midst of its second wave of the coronavirus disease 2019 (Covid-19), which started as an outbreak first reported in December 2019, Wuhan City, the capital of Hubei Province in China. Then soon enough, it was declared as a public health emergency of international concern on January 30, 2020 by WHO and a pandemic on March 11, 2020. While initially greater emphasis was laid on the elderly and people with co-morbidities such as diabetes mellitus, hypertension, obesity, and immune-compromised states as being at high risk of contracting the Covid-19 disease and/or dying of it, but by now, it is clear that being male is also a factor. Data and studies from different countries across the globe involving China, the United States of America, and European nations such as Italy have showed that although there is no difference based on sex in the number of cases testing positive for the virus, more men died from the virus, and the case-fatality ratio is greater among men than women. Women are infected by the virus as frequently as men but men are more likely to contract severe forms of disease and succumb to it. The reason behind this sex-biased mortality seen in Covid-19 cannot be explained by a single genetic or social factor. The present short communication aims at enumerating the possible reasons behind this gender-biased pandemic.

7.
Bioorg Med Chem Lett ; 21(3): 947-51, 2011 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-21232954

RESUMO

Structure-activity relationship studies were conducted to reduce CYP2D6-mediated metabolism in a series of indene H(1)-antihistamines. Reductions in pK(a) via incorporation of a ß-fluoro substituent or a heteroaryl moiety were shown to reduce contributions to metabolism through this pathway. Several compounds, including 8l, 8o, and 12f were identified with promising primary in vitro profiles and reduced biotransformation via CYP2D6.


Assuntos
Citocromo P-450 CYP2D6/química , Antagonistas dos Receptores Histamínicos H1/química , Indenos/química , Pirazinas/química , Receptores Histamínicos H1/química , Biotransformação , Citocromo P-450 CYP2D6/metabolismo , Antagonistas dos Receptores Histamínicos H1/síntese química , Antagonistas dos Receptores Histamínicos H1/farmacocinética , Indenos/síntese química , Indenos/farmacocinética , Pirazinas/síntese química , Pirazinas/farmacocinética , Receptores Histamínicos H1/metabolismo , Relação Estrutura-Atividade
8.
Bioorg Med Chem Lett ; 20(9): 2916-9, 2010 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-20347297

RESUMO

A series of 2-(3-aminopiperidine)-benzimidazoles were identified as selective H(1)-antihistamines for evaluation as potential sedative hypnotics. Representative compounds showed improved hERG selectivity over a previously identified 2-aminobenzimidazole series. While hERG activity could be modulated via manipulation of the benzimidazole N1 substituent, this approach led to a reduction in CNS exposure for the more selective compounds. One example, 9q, retained a suitable selectivity profile with CNS exposure equivalent to known centrally active H(1)-antihistamines.


Assuntos
Benzimidazóis/química , Sistema Nervoso Central/efeitos dos fármacos , Antagonistas dos Receptores Histamínicos H1/química , Distúrbios do Início e da Manutenção do Sono/tratamento farmacológico , Benzimidazóis/síntese química , Benzimidazóis/uso terapêutico , Descoberta de Drogas , Canal de Potássio ERG1 , Canais de Potássio Éter-A-Go-Go/metabolismo , Antagonistas dos Receptores Histamínicos H1/síntese química , Antagonistas dos Receptores Histamínicos H1/uso terapêutico , Humanos , Relação Estrutura-Atividade
9.
Bioorg Med Chem Lett ; 20(8): 2629-33, 2010 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-20227880

RESUMO

A series of indene analogs of the H(1)-antihistamine (-)-R-dimethindene was evaluated for selectivity in the search for potentially improved sedative-hypnotics. Variation of the 6-substitutent in the indene core in combination with a pendant electron rich heterocycle led to the identification of several potent H(1)-antihistamines with desirable selectivity over CYP enzymes, the M(1) muscarinic receptor and the hERG channel. These compounds were candidates for further ADME profiling and in vivo evaluation.


Assuntos
Antagonistas dos Receptores Histamínicos/uso terapêutico , Indenos/uso terapêutico , Distúrbios do Início e da Manutenção do Sono/tratamento farmacológico , Antagonistas dos Receptores Histamínicos/química , Antagonistas dos Receptores Histamínicos/farmacologia , Humanos , Indenos/química , Indenos/farmacologia
10.
Bioorg Med Chem Lett ; 20(19): 5874-8, 2010 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-20800486

RESUMO

Analogs of the known H(1)-antihistamine R-dimethindene with suitable selectivity for key GPCRs, P450 enzymes and hERG channel were assessed for metabolism profile and in vivo properties. Several analogs were determined to exhibit diverse metabolism. One of these compounds, 10a, showed equivalent efficacy in a rat EEG/EMG model to a previously identified clinical candidate and a potentially superior pharmacokinetic profile as determined from a human microdose study.


Assuntos
Antagonistas dos Receptores Histamínicos H1/química , Indenos/química , Piridazinas/química , Receptores Histamínicos H1/química , Distúrbios do Início e da Manutenção do Sono/tratamento farmacológico , Animais , Citocromo P-450 CYP2D6/metabolismo , Dimetideno/química , Eletroencefalografia , Antagonistas dos Receptores Histamínicos H1/farmacocinética , Antagonistas dos Receptores Histamínicos H1/uso terapêutico , Humanos , Indenos/farmacocinética , Indenos/uso terapêutico , Microssomos Hepáticos/metabolismo , Modelos Animais , Piridazinas/farmacocinética , Piridazinas/uso terapêutico , Ratos , Receptores Histamínicos H1/metabolismo , Relação Estrutura-Atividade
11.
Bioorg Med Chem Lett ; 20(7): 2316-20, 2010 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-20188547

RESUMO

SAR of lead benzothiophene H(1)-antihistamine 2 was explored to identify backup candidates with suitable pharmacokinetic profiles for an insomnia program. Several potent and selective H(1)-antihistamines with a range of projected half-lives in humans were identified. Compound 16d had a suitable human half-life as demonstrated in a human microdose study, but variability in pharmacokinetic profile, attributed to metabolic clearance, prevented further development of this compound. Compound 28b demonstrated lower predicted clearance in preclinical studies, and may represent a more suitable backup compound.


Assuntos
Antagonistas dos Receptores Histamínicos H1/farmacologia , Antagonistas dos Receptores Histamínicos H1/farmacocinética , Distúrbios do Início e da Manutenção do Sono/tratamento farmacológico , Tiofenos/farmacologia , Tiofenos/farmacocinética , Antagonistas dos Receptores Histamínicos H1/química , Antagonistas dos Receptores Histamínicos H1/uso terapêutico , Humanos , Receptores Histamínicos H1/metabolismo , Relação Estrutura-Atividade , Tiofenos/química , Tiofenos/uso terapêutico
12.
Br J Clin Pharmacol ; 67(3): 288-98, 2009 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-19523012

RESUMO

AIMS: To evaluate the pharmacokinetics (PK) of five H(1) receptor antagonists in human volunteers after a single oral and intravenous (i.v.) microdose (0.1 mg). METHODS: Five H(1) receptor antagonists, namely NBI-1, NBI-2, NBI-3, NBI-4 and diphenhydramine, were administered to human volunteers as a single 0.1-mg oral and i.v. dose. Blood samples were collected up to 48 h, and the parent compound in the plasma extract was quantified by high-performance liquid chromatography and accelerator mass spectroscopy. RESULTS: The median clearance (CL), apparent volume of distribution (V(d)) and apparent terminal elimination half-life (t(1/2)) of diphenhydramine after an i.v. microdose were 24.7 l h(-1), 302 l and 9.3 h, and the oral C(max) and AUC(0-infinity) were 0.195 ng ml(-1) and 1.52 ng h ml(-1), respectively. These data were consistent with previously published diphenhydramine data at 500 times the microdose. The rank order of oral bioavailability of the five compounds was as follows: NBI-2 > NBI-1 > NBI-3 > diphenhydramine > NBI-4, whereas the rank order for CL was NBI-4 > diphenhydramine > NBI-1 > NBI-3 > NBI-2. CONCLUSIONS: Human microdosing provided estimates of clinical PK of four structurally related compounds, which were deemed useful for compound selection.


Assuntos
Antagonistas dos Receptores Histamínicos H1/farmacocinética , Administração Oral , Adulto , Cromatografia Líquida de Alta Pressão , Estudos Cross-Over , Relação Dose-Resposta a Droga , Antagonistas dos Receptores Histamínicos H1/administração & dosagem , Humanos , Injeções Intravenosas , Masculino , Pessoa de Meia-Idade , Adulto Jovem
13.
Med Pharm Rep ; 92(3): 282-287, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31460511

RESUMO

INTRODUCTION: Odontogenic cysts are distinct entities and quite a common occurrence in the jaw bones. These are individual lesions which arise from the same odontogenic apparatus but with varying pathogenesis. Cytokeratins are integral components in tooth development and are expressed across the odontogenic tissues in physiological and pathological states. AIM: To elucidate the role of cytokeratin-7 in the pathogenesis of odontogenic cysts by immunohistochemistry. METHOD: Cytokeratin-7 (CK-7) was assessed in 39 cases of odontogenic lesions retrieved from the archival files which included 15 cases of dentigerous cysts (DC), 12 cases of odontogenic keratocysts (OKC) and 12 cases of radicular cysts (RC) and also 8 cases of control specimens. STATISTICAL ANALYSIS: Results obtained were statistically analyzed using chi-square test to assess the association between different odontogenic cysts used in this study and Cytokeration-7 staining. The difference was considered to be of statistical significance if the p value was ≤ 0.05. RESULTS: CK7 expression was maximum in dentigerous cycts (66.66%) followed by radicular cysts (41.66%) and odontogenic keratocysts (16.6%). On evaluation of staining and expression pattern, highest positivity is shown in dentigerous cysts and the positivity is seen in suprabasal (60%) and superficial layers (40%) whereas radicular cysts and odontogenic keratocysts showed positivity in superficial and spinous layers. CONCLUSION: Cytokeratin-7 expression correlates with the degree of differentiation of the epithelium. So the cysts with a well-differentiated epithelium (RC and DC) express CK-7, while the cysts with a less well-differentiated epithelium (OKC) show slight positivity. Thus it can be useful to differentiate OKC from DC and RC.

14.
Bioorg Med Chem Lett ; 18(11): 3301-5, 2008 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-18442910

RESUMO

Incorporation of a carboxylic acid into a series of uracil derivatives as hGnRH-R antagonists resulted in a significant reduction of CYP3A4 inhibitory activity. Highly potent hGnRH antagonists with low CYP3A4 inhibitory liability, such as 8a and 8d, were identified. Thus, 8a had a K(i) of 2.2 nM at GnRH-R and an IC(50) of 36 microM at CYP3A4.


Assuntos
Inibidores do Citocromo P-450 CYP3A , Hormônio Liberador de Gonadotropina/antagonistas & inibidores , Receptores LHRH/antagonistas & inibidores , Uracila/análogos & derivados , Uracila/síntese química , Animais , Citocromo P-450 CYP3A , Haplorrinos , Humanos , Concentração Inibidora 50 , Estrutura Molecular , Ratos , Relação Estrutura-Atividade , Uracila/farmacocinética
15.
Bioorg Med Chem Lett ; 18(1): 129-36, 2008 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-18032040

RESUMO

A series of trans-4-phenylpyrrolidine-3-carboxamides were synthesized and characterized as potent ligands of the human melanocortin-4 receptor. Interestingly, a pair of diastereoisomers 13b displayed potent functional agonist and antagonist activity, respectively. Thus, the 3S,4R-pyrrolidine 13b-1 possessed a Ki of 1.0 nM and an EC50 of 3.8 nM, while its 3R,4S-isomer 13b-2 exhibited a Ki of 4.7 and an IC50 of 64 nM. Both compounds were highly selective over other melanocortin receptor subtypes. The MC4R agonist 13b-1 also demonstrated efficacy in a diet-induced obesity model in rats.


Assuntos
Pirrolidinas/química , Pirrolidinas/farmacologia , Receptor Tipo 4 de Melanocortina/agonistas , Receptor Tipo 4 de Melanocortina/antagonistas & inibidores , Amidas/síntese química , Amidas/química , Amidas/farmacologia , Animais , Relação Dose-Resposta a Droga , Ingestão de Alimentos/efeitos dos fármacos , Humanos , Cinética , Masculino , Pirrolidinas/síntese química , Pirrolidinas/farmacocinética , Ratos , Estereoisomerismo , Relação Estrutura-Atividade
17.
J Med Chem ; 50(25): 6356-66, 2007 Dec 13.
Artigo em Inglês | MEDLINE | ID: mdl-17994683

RESUMO

Benzylamine and pyridinemethylamine derivatives were synthesized and characterized as potent and selective antagonists of the melanocortin-4 receptor (MC4R). These compounds were also profiled in rodents for their pharmacokinetic properties. Two compounds with diversified profiles in chemical structure, pharmacological activities, and pharmacokinetics, 10 and 12b, showed efficacy in an established murine cachexia model. For example, 12b had a K(i) value of 3.4 nM at MC4R, was more than 200-fold selective over MC3R, and had a good pharmacokinetic profile in mice, including high brain penetration. Moreover, 12b was able to stimulate food intake in the tumor-bearing mice and reverse their lean body mass loss. Our results provided further evidence that a potent and selective MC4R antagonist with appropriate pharmacokinetic properties might potentially be useful for the treatment of cancer cachexia.


Assuntos
Amidas/síntese química , Benzilaminas/síntese química , Piperazinas/síntese química , Piridinas/síntese química , Receptor Tipo 4 de Melanocortina/antagonistas & inibidores , Amidas/farmacocinética , Amidas/farmacologia , Animais , Benzilaminas/farmacocinética , Benzilaminas/farmacologia , Caquexia/tratamento farmacológico , Caquexia/etiologia , Carcinoma Pulmonar de Lewis/complicações , Linhagem Celular , Cristalografia por Raios X , AMP Cíclico/metabolismo , Desenho de Fármacos , Ingestão de Alimentos/efeitos dos fármacos , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Modelos Moleculares , Transplante de Neoplasias , Piperazinas/farmacocinética , Piperazinas/farmacologia , Piridinas/farmacocinética , Piridinas/farmacologia , Estereoisomerismo , Relação Estrutura-Atividade
18.
J Med Chem ; 50(22): 5249-52, 2007 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-17918824

RESUMO

A potent and selective antagonist of the melanocortin-4 receptor, 1-[2-[(1S)-(3-dimethylaminopropionyl)amino-2-methylpropyl]-6-methylphenyl]-4-[(2R)-methyl-3-(4-chlorophenyl)propionyl]piperazine (10d), was identified from a series piperazinebenzylamine attached with a N,N-dimethyl-beta-alanine side chain. This compound possessed high water solubility and exhibited good metabolic profiles. In animals, 10d showed moderate to good oral bioavailability and promoted food intake in tumor-bearing mice after oral administration.


Assuntos
Caquexia/tratamento farmacológico , Piperazinas/síntese química , Receptor Tipo 4 de Melanocortina/antagonistas & inibidores , beta-Alanina/análogos & derivados , Administração Oral , Animais , Disponibilidade Biológica , Caquexia/etiologia , AMP Cíclico/metabolismo , Cães , Ingestão de Alimentos/efeitos dos fármacos , Humanos , Macaca mulatta , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Microssomos Hepáticos/metabolismo , Transplante de Neoplasias , Neoplasias Experimentais/complicações , Piperazinas/farmacocinética , Piperazinas/farmacologia , Ensaio Radioligante , Ratos , Ratos Sprague-Dawley , Solubilidade , Estereoisomerismo , Relação Estrutura-Atividade , beta-Alanina/síntese química , beta-Alanina/farmacocinética , beta-Alanina/farmacologia
19.
J Med Chem ; 49(13): 3753-6, 2006 Jun 29.
Artigo em Inglês | MEDLINE | ID: mdl-16789729

RESUMO

Melanin-concentrating hormone receptor antagonists containing thieno- and a benzopyridazinone cores were designed and tested as potential anorectic agents. These ligands showed high affinity for the receptor, potent functional activity in vitro, and good oral bioavailabilty in rats. The thiophene analogue exhibited low iv clearance, long half-life, and high brain penetration. In obese rats, the thienopyridazinone demonstrated a dose-dependent reduction in feeding and body weight with doses between 1 and 10 mg kg-1.


Assuntos
Depressores do Apetite/síntese química , Piridazinas/síntese química , Receptores de Somatostatina/antagonistas & inibidores , Tiofenos/síntese química , Animais , Depressores do Apetite/farmacocinética , Depressores do Apetite/farmacologia , Disponibilidade Biológica , Peso Corporal/efeitos dos fármacos , Encéfalo/metabolismo , Ingestão de Alimentos/efeitos dos fármacos , Meia-Vida , Masculino , Obesidade/tratamento farmacológico , Permeabilidade , Piridazinas/química , Piridazinas/farmacologia , Ratos , Ratos Sprague-Dawley , Estereoisomerismo , Relação Estrutura-Atividade , Tiofenos/farmacocinética , Tiofenos/farmacologia
20.
Toxicol In Vitro ; 20(2): 154-62, 2006 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-16321501

RESUMO

SU5416, 3-(3,5-dimethyl-1H-pyrrol-2-ylmethylene)-1,3-dihydro-indol-2-one, is a potent inhibitor of vascular endothelial growth factor (VEGF) receptor tyrosine kinase, Flk-1/KDR (fetal liver kinase 1/kinase insert domain-containing receptor), also known as VEGF receptor 2 (VEGFR2). It was the first VEGFR2 inhibitor to enter clinical trials for the treatment of colorectal and non-small cell lung cancers. Pre-clinical evaluation of SU5416 included studies related to the distribution, metabolism and excretion of this compound. These studies have provided information useful in understanding the disposition and metabolism of the indolinone class of chemicals, which has not been studied previously with therapeutic intent. The lessons we learned from SU5416 have been successfully applied in developing next generation indolinone compounds targeting tumor angiogenesis.


Assuntos
Inibidores da Angiogênese/farmacocinética , Indóis/farmacocinética , Pirróis/farmacocinética , Inibidores da Angiogênese/administração & dosagem , Animais , Autorradiografia , Biotransformação , Proteínas Sanguíneas/metabolismo , Sistema Enzimático do Citocromo P-450/metabolismo , Avaliação Pré-Clínica de Medicamentos , Humanos , Indóis/administração & dosagem , Injeções Intravenosas , Ligação Proteica , Pirróis/administração & dosagem , Especificidade da Espécie
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