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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.
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Acromegalia , Hormona de Crecimiento Humana , Acromegalia/tratamiento farmacológico , Método Doble Ciego , Hormona del Crecimiento/metabolismo , Voluntarios Sanos , Hormona de Crecimiento Humana/metabolismo , Humanos , Factor I del Crecimiento Similar a la Insulina/metabolismo , MasculinoRESUMEN
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)].
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Tetrabenazina/análogos & derivados , Valina/análogos & derivados , Proteínas de Transporte Vesicular de Monoaminas/antagonistas & inhibidores , Proteínas de Transporte Vesicular de Monoaminas/metabolismo , Animales , Plaquetas/efectos de los fármacos , Plaquetas/metabolismo , Células CHO , Cuerpo Estriado/efectos de los fármacos , Cuerpo Estriado/metabolismo , Cricetinae , Cricetulus , Células HEK293 , Humanos , Unión Proteica/efectos de los fármacos , Unión Proteica/fisiología , Ratas , Tetrabenazina/metabolismo , Tetrabenazina/farmacología , Valina/metabolismo , Valina/farmacologíaRESUMEN
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.
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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.
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Acromegalia , Hormona de Crecimiento Humana , Humanos , Acromegalia/tratamiento farmacológico , Acromegalia/metabolismo , Octreótido/uso terapéutico , Factor I del Crecimiento Similar a la Insulina/metabolismo , Estudios Prospectivos , Péptidos Cíclicos/efectos adversos , Resultado del TratamientoRESUMEN
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.
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Bencimidazoles/síntesis química , Antagonistas de los Receptores Histamínicos H1/farmacología , Trastornos del Inicio y del Mantenimiento del Sueño/tratamiento farmacológico , Bencimidazoles/farmacología , Sistema Nervioso Central/efectos de los fármacos , Diseño de Fármacos , Canal de Potasio ERG1 , Electrofisiología/métodos , Canales de Potasio Éter-A-Go-Go/química , Humanos , Hipnóticos y Sedantes/farmacología , Concentración 50 Inhibidora , Cinética , Microsomas Hepáticos/efectos de los fármacos , Modelos Químicos , Morfolinas/química , Nitrógeno/química , Piperidinas/química , Receptores Histamínicos H1/química , Relación Estructura-ActividadRESUMEN
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.
RESUMEN
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.
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Citocromo P-450 CYP2D6/química , Antagonistas de los Receptores Histamínicos H1/química , Indenos/química , Pirazinas/química , Receptores Histamínicos H1/química , Biotransformación , Citocromo P-450 CYP2D6/metabolismo , Antagonistas de los Receptores Histamínicos H1/síntesis química , Antagonistas de los Receptores Histamínicos H1/farmacocinética , Indenos/síntesis química , Indenos/farmacocinética , Pirazinas/síntesis química , Pirazinas/farmacocinética , Receptores Histamínicos H1/metabolismo , Relación Estructura-ActividadRESUMEN
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.
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Bencimidazoles/química , Sistema Nervioso Central/efectos de los fármacos , Antagonistas de los Receptores Histamínicos H1/química , Trastornos del Inicio y del Mantenimiento del Sueño/tratamiento farmacológico , Bencimidazoles/síntesis química , Bencimidazoles/uso terapéutico , Descubrimiento de Drogas , Canal de Potasio ERG1 , Canales de Potasio Éter-A-Go-Go/metabolismo , Antagonistas de los Receptores Histamínicos H1/síntesis química , Antagonistas de los Receptores Histamínicos H1/uso terapéutico , Humanos , Relación Estructura-ActividadRESUMEN
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.
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Antagonistas de los Receptores Histamínicos/uso terapéutico , Indenos/uso terapéutico , Trastornos del Inicio y del Mantenimiento del Sueño/tratamiento farmacológico , Antagonistas de los Receptores Histamínicos/química , Antagonistas de los Receptores Histamínicos/farmacología , Humanos , Indenos/química , Indenos/farmacologíaRESUMEN
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.
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Antagonistas de los Receptores Histamínicos H1/química , Indenos/química , Piridazinas/química , Receptores Histamínicos H1/química , Trastornos del Inicio y del Mantenimiento del Sueño/tratamiento farmacológico , Animales , Citocromo P-450 CYP2D6/metabolismo , Dimetindeno/química , Electroencefalografía , Antagonistas de los Receptores Histamínicos H1/farmacocinética , Antagonistas de los Receptores Histamínicos H1/uso terapéutico , Humanos , Indenos/farmacocinética , Indenos/uso terapéutico , Microsomas Hepáticos/metabolismo , Modelos Animales , Piridazinas/farmacocinética , Piridazinas/uso terapéutico , Ratas , Receptores Histamínicos H1/metabolismo , Relación Estructura-ActividadRESUMEN
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.
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Antagonistas de los Receptores Histamínicos H1/farmacología , Antagonistas de los Receptores Histamínicos H1/farmacocinética , Trastornos del Inicio y del Mantenimiento del Sueño/tratamiento farmacológico , Tiofenos/farmacología , Tiofenos/farmacocinética , Antagonistas de los Receptores Histamínicos H1/química , Antagonistas de los Receptores Histamínicos H1/uso terapéutico , Humanos , Receptores Histamínicos H1/metabolismo , Relación Estructura-Actividad , Tiofenos/química , Tiofenos/uso terapéuticoRESUMEN
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.
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Antagonistas de los Receptores Histamínicos H1/farmacocinética , Administración Oral , Adulto , Cromatografía Líquida de Alta Presión , Estudios Cruzados , Relación Dosis-Respuesta a Droga , Antagonistas de los Receptores Histamínicos H1/administración & dosificación , Humanos , Inyecciones Intravenosas , Masculino , Persona de Mediana Edad , Adulto JovenRESUMEN
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.
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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.
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Pirrolidinas/química , Pirrolidinas/farmacología , Receptor de Melanocortina Tipo 4/agonistas , Receptor de Melanocortina Tipo 4/antagonistas & inhibidores , Amidas/síntesis química , Amidas/química , Amidas/farmacología , Animales , Relación Dosis-Respuesta a Droga , Ingestión de Alimentos/efectos de los fármacos , Humanos , Cinética , Masculino , Pirrolidinas/síntesis química , Pirrolidinas/farmacocinética , Ratas , Estereoisomerismo , Relación Estructura-ActividadRESUMEN
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.
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Inhibidores del Citocromo P-450 CYP3A , Hormona Liberadora de Gonadotropina/antagonistas & inhibidores , Receptores LHRH/antagonistas & inhibidores , Uracilo/análogos & derivados , Uracilo/síntesis química , Animales , Citocromo P-450 CYP3A , Haplorrinos , Humanos , Concentración 50 Inhibidora , Estructura Molecular , Ratas , Relación Estructura-Actividad , Uracilo/farmacocinéticaRESUMEN
A novel series of potent zwitterionic uracil GnRH antagonists were discovered that showed reduced liability for CYP3A4 enzyme inhibition.
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Química Farmacéutica/métodos , Citocromo P-450 CYP3A/química , Iones , Receptores LHRH/antagonistas & inhibidores , Uracilo/análogos & derivados , Diseño de Fármacos , Hormona Liberadora de Gonadotropina/química , Humanos , Cinética , Modelos Químicos , Estructura Molecular , Péptidos/química , Estereoisomerismo , Relación Estructura-Actividad , Uracilo/químicaRESUMEN
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.
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Amidas/síntesis química , Bencilaminas/síntesis química , Piperazinas/síntesis química , Piridinas/síntesis química , Receptor de Melanocortina Tipo 4/antagonistas & inhibidores , Amidas/farmacocinética , Amidas/farmacología , Animales , Bencilaminas/farmacocinética , Bencilaminas/farmacología , Caquexia/tratamiento farmacológico , Caquexia/etiología , Carcinoma Pulmonar de Lewis/complicaciones , Línea Celular , Cristalografía por Rayos X , AMP Cíclico/metabolismo , Diseño de Fármacos , Ingestión de Alimentos/efectos de los fármacos , Humanos , Masculino , Ratones , Ratones Endogámicos C57BL , Modelos Moleculares , Trasplante de Neoplasias , Piperazinas/farmacocinética , Piperazinas/farmacología , Piridinas/farmacocinética , Piridinas/farmacología , Estereoisomerismo , Relación Estructura-ActividadRESUMEN
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.
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Caquexia/tratamiento farmacológico , Piperazinas/síntesis química , Receptor de Melanocortina Tipo 4/antagonistas & inhibidores , beta-Alanina/análogos & derivados , Administración Oral , Animales , Disponibilidad Biológica , Caquexia/etiología , AMP Cíclico/metabolismo , Perros , Ingestión de Alimentos/efectos de los fármacos , Humanos , Macaca mulatta , Masculino , Ratones , Ratones Endogámicos C57BL , Microsomas Hepáticos/metabolismo , Trasplante de Neoplasias , Neoplasias Experimentales/complicaciones , Piperazinas/farmacocinética , Piperazinas/farmacología , Ensayo de Unión Radioligante , Ratas , Ratas Sprague-Dawley , Solubilidad , Estereoisomerismo , Relación Estructura-Actividad , beta-Alanina/síntesis química , beta-Alanina/farmacocinética , beta-Alanina/farmacologíaRESUMEN
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.
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Depresores del Apetito/síntesis química , Piridazinas/síntesis química , Receptores de Somatostatina/antagonistas & inhibidores , Tiofenos/síntesis química , Animales , Depresores del Apetito/farmacocinética , Depresores del Apetito/farmacología , Disponibilidad Biológica , Peso Corporal/efectos de los fármacos , Encéfalo/metabolismo , Ingestión de Alimentos/efectos de los fármacos , Semivida , Masculino , Obesidad/tratamiento farmacológico , Permeabilidad , Piridazinas/química , Piridazinas/farmacología , Ratas , Ratas Sprague-Dawley , Estereoisomerismo , Relación Estructura-Actividad , Tiofenos/farmacocinética , Tiofenos/farmacologíaRESUMEN
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.