RESUMEN
A structure-activity relationship study was undertaken to address the lack of oral exposure of the H3 antagonist 1, which incorporated an arylketone. Among a number of sub-series, the 4H-pyrido[1,2-a]pyrimidin-4-one analog 21 showed an improved PK profile in rat and mouse and was active in an obesity model. The pyrimidin-4-one proved to be a novel and useful ketone bioisostere.
Asunto(s)
Antagonistas de los Receptores Histamínicos H3/farmacocinética , Tiadiazoles/farmacología , Administración Oral , Animales , Cetonas , Obesidad/tratamiento farmacológico , Ratas , Relación Estructura-Actividad , Tiadiazoles/farmacocinéticaRESUMEN
The synthesis and SAR of a novel series of 4-azabenzoxazole histamine H(3) antagonists is described. Introduction of substituted phenyl, pyridyl and fused heterocyclic groups to the 6-position of the 4-azabenzoxazole core gave a series of compounds with good H(3) antagonist activity in both ex vivo and in vivo assays.
Asunto(s)
Benzoxazoles/química , Benzoxazoles/farmacología , Antagonistas de los Receptores Histamínicos H3/química , Antagonistas de los Receptores Histamínicos H3/farmacología , Receptores Histamínicos H3/metabolismo , Animales , Compuestos Aza/síntesis química , Compuestos Aza/química , Compuestos Aza/farmacocinética , Compuestos Aza/farmacología , Benzoxazoles/síntesis química , Benzoxazoles/farmacocinética , Antagonistas de los Receptores Histamínicos H3/síntesis química , Antagonistas de los Receptores Histamínicos H3/farmacocinética , Humanos , Ratones , Ratas , Relación Estructura-ActividadRESUMEN
A series of novel 2-piperidinopiperidine thiadiazoles were synthesized and evaluated as new leads of histamine H3 receptor antagonists. The 4-(5-([1,4'-bipiperidin]-1'-yl)-1,3,4-thiadiazol-2-yl)-2-(pyridin-2-yl)morpholine (5u) displayed excellent potency and ex vivo receptor occupancy. Compound 5u was also evaluated in vivo for antidiabetic efficacy in STZ diet-induced obesity type 2 diabetic mice for 2 or 12 days. Non-fasting glucose levels were significantly reduced as compared with vehicle-treated mice. In addition, 5u dose dependently blocked the increase of HbA1c after 12 days of treatment.
RESUMEN
A series of 2-piperidinopiperidine-5-arylthiadiazoles was synthesized and subjected to a structure-activity relationship (SAR) investigation. The potency of this series was improved to the single digit nanomolar range. The key analogs were shown to be free of P450 issues, and they also maintained good ex vivo activity and brain penetration.
Asunto(s)
Antagonistas de los Receptores Histamínicos/química , Antagonistas de los Receptores Histamínicos/farmacología , Receptores Histamínicos H3/metabolismo , Tiadiazoles/química , Tiadiazoles/farmacología , Animales , Encéfalo/metabolismo , Antagonistas de los Receptores Histamínicos/farmacocinética , Humanos , Ratones , Ratas , Relación Estructura-Actividad , Tiadiazoles/farmacocinéticaRESUMEN
A structure-activity relationship study of the lead piperazinylcarbonylpiperidine compound 3 resulted in the identification of 4-benzimidazolyl-piperidinylcarbonyl-piperidine 6h as a histamine-3 (H(3)) receptor antagonist. Additional optimization of 6h led to the identification of compounds 11i-k with K(i) Asunto(s)
Antagonistas de los Receptores Histamínicos H3/síntesis química
, Antagonistas de los Receptores Histamínicos H3/farmacología
, Piperidinas/síntesis química
, Piperidinas/farmacología
, Relación Estructura-Actividad
RESUMEN
Structural features of the substituted 4-piperidinyl urea analogs 1, responsible for the H3 antagonist activity, have been identified. Structure-activity relationship of the H3 receptor affinity, hERG ion channel inhibitory activity and their separation is described. Preliminary pharmacokinetic evaluation of the compounds of the series is addressed.
Asunto(s)
Canales de Potasio Éter-A-Go-Go/antagonistas & inhibidores , Antagonistas de los Receptores Histamínicos/farmacología , Piperidinas/farmacología , Receptores Histamínicos H3/metabolismo , Urea/farmacología , Animales , Canales de Potasio Éter-A-Go-Go/metabolismo , Antagonistas de los Receptores Histamínicos/química , Antagonistas de los Receptores Histamínicos/farmacocinética , Humanos , Piperidinas/química , Piperidinas/farmacocinética , Ratas , Relación Estructura-Actividad , Urea/química , Urea/farmacocinéticaRESUMEN
A series of 2-(1,4'-bipiperidine-1'-yl)thiazolopyridines was synthesized and evaluated as a new lead of non-imidazole histamine H(3) receptor antagonists. Introduction of diversity at the 6-position of the pyridine ring was designed to enhance in vitro potency and decrease hERG activity. The structure-activity relationships for these new thiazolopyridine antagonists are discussed.
Asunto(s)
Antagonistas de los Receptores Histamínicos/química , Piridinas/química , Receptores Histamínicos H3/química , Animales , Haplorrinos , Antagonistas de los Receptores Histamínicos/síntesis química , Antagonistas de los Receptores Histamínicos/farmacocinética , Humanos , Ratones , Ratones Endogámicos ICR , Microsomas Hepáticos/metabolismo , Piridinas/síntesis química , Piridinas/farmacocinética , Ratas , Receptores Histamínicos H3/metabolismo , Proteínas Recombinantes/química , Proteínas Recombinantes/metabolismo , Relación Estructura-Actividad , Transactivadores/metabolismo , Regulador Transcripcional ERGRESUMEN
In the late 1980's reports linking the non-sedating antihistamines terfenadine and astemizole with torsades de pointes, a form of ventricular tachyarrhythmia that can degenerate into ventricular fibrillation and sudden death, appeared in the clinical literature. A substantial body of evidence demonstrates that the arrhythmogenic effect of these cardiotoxic antihistamines, as well as a number of structurally related compounds, results from prolongation of the QT interval due to suppression of specific delayed rectifier ventricular K+ currents via blockade of the hERG-IKr channel. In order to better understand the structural requirements for hERG and H(1) binding for terfenadine, a series of analogs of terfenadine has been prepared and studied in both in vitro and in vivo hERG and H(1) assays.
Asunto(s)
Antagonistas de los Receptores Histamínicos H1 no Sedantes/química , Receptores Histamínicos H1/metabolismo , Terfenadina/análogos & derivados , Transactivadores/metabolismo , Animales , Electrocardiografía , Cobayas , Antagonistas de los Receptores Histamínicos H1 no Sedantes/síntesis química , Antagonistas de los Receptores Histamínicos H1 no Sedantes/farmacología , Humanos , Unión Proteica , Relación Estructura-Actividad , Terfenadina/química , Terfenadina/farmacología , Regulador Transcripcional ERGRESUMEN
A series of non-imidazole histamine H(3) receptor antagonists based on the (3-phenoxypropyl)amine motif, which is a common pharmacophore for H(3) antagonists, has been identified. A preliminary SAR study around the amine moiety has identified 8a as a potent H(3) antagonist possessing a good pharmacokinetic profile in the rat.
Asunto(s)
Aminas/síntesis química , Aminas/farmacología , Bencimidazoles/síntesis química , Bencimidazoles/farmacología , Receptores Histamínicos H3/efectos de los fármacos , Aminas/química , Animales , Bencimidazoles/química , Técnicas Químicas Combinatorias , Estructura Molecular , Ratas , Relación Estructura-ActividadRESUMEN
A novel series of histamine H3 receptor antagonists based on the 4-[(1H-imidazol-4-yl)methyl]piperidine template displaying low CYP2D6 and CYP3A4 inhibitory profiles has been identified. Structural features responsible for the reduction of P450 activity, a typical liability of 4-substituted imidazoles, have been established.
Asunto(s)
Inhibidores Enzimáticos del Citocromo P-450 , Inhibidores Enzimáticos/farmacología , Antagonistas de los Receptores Histamínicos/farmacología , Imidazoles/farmacología , Piperidinas/farmacología , Receptores Histamínicos H3/efectos de los fármacos , Animales , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/química , Cobayas , Haplorrinos , Antagonistas de los Receptores Histamínicos/síntesis química , Antagonistas de los Receptores Histamínicos/química , Humanos , Imidazoles/síntesis química , Imidazoles/química , Estructura Molecular , Piperidinas/síntesis química , Piperidinas/química , Ratas , Relación Estructura-Actividad , Distribución TisularRESUMEN
We report the discovery of novel histamine H(3) receptor antagonists based on 4-[(1H-imidazol-4-yl)methyl]piperidine. The most potent compounds in the series (e.g., 7) result from the attachment of a substituted aniline amide to the main pharmacophore piperidine via a two-methylene linker.
Asunto(s)
Antagonistas de los Receptores Histamínicos/farmacología , Imidazoles/farmacología , Piperidinas/farmacología , Receptores Histamínicos H3/efectos de los fármacos , Inhibidores del Citocromo P-450 CYP2D6 , Evaluación Preclínica de Medicamentos , Antagonistas de los Receptores Histamínicos/síntesis química , Antagonistas de los Receptores Histamínicos/química , Humanos , Imidazoles/síntesis química , Imidazoles/química , Técnicas In Vitro , Estructura Molecular , Piperidinas/síntesis química , Piperidinas/química , Relación Estructura-ActividadRESUMEN
Combining the first generation H(1) antihistamine chlorpheniramine (1) with H(3) ligands of the alkylamine type has led to the identification of compound 9d, a dual ligand of both the H(1) and H(3) receptors.
Asunto(s)
Clorfeniramina/análogos & derivados , Antagonistas de los Receptores Histamínicos/química , Antagonistas de los Receptores Histamínicos/farmacología , Receptores Histamínicos H1/metabolismo , Receptores Histamínicos H3/metabolismo , Animales , Clorfeniramina/metabolismo , Clorfeniramina/farmacología , Cobayas , Antagonistas de los Receptores Histamínicos/metabolismo , Antagonistas de los Receptores Histamínicos H1/química , Antagonistas de los Receptores Histamínicos H1/metabolismo , Antagonistas de los Receptores Histamínicos H1/farmacología , Ligandos , Relación Estructura-ActividadRESUMEN
We present the pharmacological and pharmacokinetic profiles of a novel histamine H3 receptor antagonist, N-(3,5-dichlorophenyl)-N'-[[4-(1H-imidazol-4-ylmethyl)phenyl]-methyl]-urea (SCH 79687). The H3-receptor binding Ki values for SCH 79687 were 1.9 and 13 nM in the rat and guinea pig (GP), respectively. The Ki values for SCH 79687 at histamine H1 and H2 receptors were greater than 1 microM. SCH 79687 showed a 41- and 82-fold binding selectivity for the H3 receptor over alpha 2A-adrenoceptors and imidazoline I2, and >500-fold H3 selectivity compared with over 60 additional receptors. The pA2 value for SCH 79687 in the GP ileum electrical field-stimulated (EFS) contraction was 9.6 +/- 0.3. Similar H3 antagonist activity was observed in the EFS cryopreserved and fresh tissue isolated human saphenous vein (HSV) assays (pKb = 9.4 +/- 0.3 and 10.1 +/- 0.4). SCH 79687 (30 nM) did not block clonidine-induced inhibition of EFS-induced contractions in HSV. SCH 79687 (ED50 = 0.3 mg/kg i.v.) attenuated (R)-alpha-methylhistamine inhibition of sympathetic hypertensive responses in the GP. At the time of activity evaluation, the GP plasma SCH 79687 concentration was 25 ng/ml at the dose of 0.3 mg/kg i.v. In feline nasal studies, combined administration of SCH 79687 (3 mg/kg i.v.) and the H1-antagonist loratadine (3 mg/kg i.v.), at individual doses that do not produce decongestion, inhibited the compound 48/80-induced congestion by 47%. The alpha-adrenergic agonist phenylpropanolamine (PPA; 1 mg/kg i.v.) also attenuated compound 48/80 nasal responses by 42%. Unlike the H3/H1 combination that did not affect blood pressure (BP), PPA (1 mg/kg i.v.) significantly increased BP compared with control animals by a maximum of 31 mm Hg. Orally, SCH 79687 (10 mg/kg) plus loratadine (10 mg/kg) also produced decongestion without effects on BP. In pharmacokinetic studies, oral dosing with SCH 79687 in the rat (10 mg/kg) and monkey (3 mg/kg) achieved plasma Cmax and area under the curve values greater than 1.5 and 12.1 microg. h/ml, respectively. SCH 79687 is an orally active H3 antagonist with a good pharmacokinetic profile that, in combination with an H1 antagonist, demonstrates decongestant efficacy comparable with oral sympathomimetic decongestants but without hypertensive liabilities.
Asunto(s)
Agonistas de los Receptores Histamínicos/farmacología , Antagonistas de los Receptores Histamínicos/farmacología , Imidazoles/farmacología , Compuestos de Fenilurea/farmacología , Receptores Histamínicos H3/metabolismo , Animales , Gatos , Interacciones Farmacológicas , Femenino , Cobayas , Haplorrinos , Agonistas de los Receptores Histamínicos/farmacocinética , Antagonistas de los Receptores Histamínicos/farmacocinética , Humanos , Íleon/efectos de los fármacos , Íleon/metabolismo , Loratadina/farmacología , Masculino , Metilhistaminas/farmacocinética , Metilhistaminas/farmacología , Descongestionantes Nasales/farmacología , Ratas , Receptores Histamínicos H3/efectos de los fármacos , Vena Safena/efectos de los fármacos , Vena Safena/metabolismoRESUMEN
We have characterized desloratadine (5H-benzo[5,6]cyclohepta[1,2-b]pyridine, 8-chloro-6,11-dihydro-11-(4-piperidinylidene), CAS 100643-71-8) as a potent antagonist of the human histamine H(1) receptor. [3H]Desloratadine bound to membranes expressing the recombinant human histamine H(1) receptor in Chinese hamster ovary cells (CHO-H(1)) in a specific and saturable manner with a K(d) of 1.1+/-0.2 nM, a B(max) of 7.9+/-2.0 pmol/mg protein, and an association rate constant of 0.011 nM(-1) x min(-1). The K(d) calculated from the kinetic measurements was 1.5 nM. Dissociation of [3H]desloratadine from the human histamine H(1) receptor was slow, with only 37% of the binding reversed at 6 h in the presence of 5 microM unlabeled desloratadine. Seventeen histamine H(1)-receptor antagonists were evaluated in competition-binding studies. Desloratadine had a K(i) of 0.9+/-0.1 nM in these competition studies. In CHO-H(1) cells, histamine stimulation resulted in a concentration-dependent increase in [Ca(2+)](i) with an EC(50) of 170+/-30 nM. After a 90-min preincubation with desloratadine, the histamine-stimulated increase in [Ca(2+)](i) was shifted to the right, with a depression of the maximal response at higher concentrations of antagonist. The apparent K(b) value was 0.2+/-0.14 nM with a slope of 1.6+/-0.1. The slow dissociation from the receptor and noncompetitive antagonism suggests that desloratadine may be a pseudoirreversible antagonist of the human histamine H(1) receptor. The mechanism of desloratadine antagonism of the human histamine H(1) receptor may help to explain the high potency and 24-h duration of action observed in clinical studies.
Asunto(s)
Antagonistas de los Receptores Histamínicos H1/farmacología , Loratadina/análogos & derivados , Loratadina/farmacología , Receptores Histamínicos H1/efectos de los fármacos , Animales , Unión Competitiva/efectos de los fármacos , Células CHO , Calcio/metabolismo , Clonación Molecular , Cricetinae , Cartilla de ADN/farmacología , Femenino , Antagonistas de los Receptores Histamínicos H1/metabolismo , Humanos , Cinética , Loratadina/metabolismo , Oligonucleótidos Antisentido/farmacología , Pirilamina/metabolismo , Receptores Histamínicos H1/metabolismoRESUMEN
A novel series of histamine H(3) receptor antagonists, based on the 4-benzyl-(1H-imidazole-4-yl) template, incorporating urea and carbamate linkers has been prepared. Compound 3j is a selective H(3) antagonist and demonstrates excellent oral plasma levels in the rat and monkey.