RESUMEN
Through an internal virtual screen at GlaxoSmithKline a distinct class of 2-phenylimidazo[1,2-a]pyridine-6-carboxamide H-PGDS inhibitors were discovered. Careful evaluation of crystal structures and SAR led to a novel, potent, and orally active imidazopyridine inhibitor of H-PGDS, 20b. Herein, describes the identification of 2 classes of inhibitors, their syntheses, and their challenges.
Asunto(s)
Descubrimiento de Drogas , Inhibidores Enzimáticos/farmacología , Relación Dosis-Respuesta a Droga , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/química , Humanos , Oxidorreductasas Intramoleculares/antagonistas & inhibidores , Oxidorreductasas Intramoleculares/metabolismo , Estructura Molecular , Relación Estructura-ActividadRESUMEN
With the goal of discovering more selective anti-inflammatory drugs, than COX inhibitors, to attenuate prostaglandin signaling, a fragment-based screen of hematopoietic prostaglandin D synthase was performed. The 76 crystallographic hits were sorted into similar groups, with the 3-cyano-quinoline 1a (FP IC50â¯=â¯220,000â¯nM, LEâ¯=â¯0.43) being a potent member of the 6,6-fused heterocyclic cluster. Employing SAR insights gained from structural comparisons of other H-PGDS fragment binding mode clusters, the initial hit 1a was converted into the 70-fold more potent quinoline 1d (IC50â¯=â¯3,100â¯nM, LEâ¯=â¯0.49). A systematic substitution of the amine moiety of 1d, utilizing structural information and array chemistry, with modifications to improve inhibitor stability, resulted in the identification of the 300-fold more active H-PGDS inhibitor tool compound 1bv (IC50â¯=â¯9.9â¯nM, LEâ¯=â¯0.42). This selective inhibitor exhibited good murine pharmacokinetics, dose-dependently attenuated PGD2 production in a mast cell degranulation assay and should be suitable to further explore H-PGDS biology.
Asunto(s)
Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/farmacología , Oxidorreductasas Intramoleculares/antagonistas & inhibidores , Lipocalinas/antagonistas & inhibidores , Quinolinas/química , Quinolinas/farmacología , Animales , Descubrimiento de Drogas , Inhibidores Enzimáticos/farmacocinética , Humanos , Oxidorreductasas Intramoleculares/química , Oxidorreductasas Intramoleculares/metabolismo , Lipocalinas/química , Lipocalinas/metabolismo , Masculino , Ratones Endogámicos C57BL , Simulación del Acoplamiento Molecular , Quinolinas/farmacocinéticaRESUMEN
A series of potent, selective and long-acting quinoline-based sulfonamide human H1 histamine receptor antagonists, designed for once-daily intranasal administration for the treatment of rhinitis were developed. Sulfonamide 33b had a slightly lower affinity for the H1 receptor than azelastine, had low oral bioavailability in the rat and dog, and was turned over to five major metabolites. Furthermore, 33b had longer duration of action than azelastine in guinea pigs, lower rat brain-penetration, and did not cause time dependent inhibition of CYP2D6 or CYP3A4. The clinical dose in humans is expected to be low (approximately 0.5mg per day) based on the clinical dose used for azelastine and a comparison of efficacy data from animal models for 33b and azelastine.
Asunto(s)
Antagonistas de los Receptores Histamínicos H1/química , Quinolinas/química , Receptores Histamínicos H1/metabolismo , Rinitis Alérgica/tratamiento farmacológico , Sulfanilamidas/química , Sulfonamidas/química , Sulfonas/química , Administración Intranasal , Animales , Encéfalo/metabolismo , Perros , Cobayas , Semivida , Antagonistas de los Receptores Histamínicos H1/farmacocinética , Antagonistas de los Receptores Histamínicos H1/uso terapéutico , Concentración 50 Inhibidora , Quinolinas/farmacocinética , Quinolinas/uso terapéutico , Ratas , Receptores Histamínicos H1/química , Rinitis Alérgica/metabolismo , Rinitis Alérgica/patología , Relación Estructura-Actividad , Sulfanilamida , Sulfanilamidas/farmacocinética , Sulfanilamidas/uso terapéutico , Sulfonamidas/farmacocinética , Sulfonamidas/uso terapéutico , Sulfonas/farmacocinética , Sulfonas/uso terapéuticoRESUMEN
A novel series of potent quinoline-based human H1 and H3 bivalent histamine receptor antagonists, suitable for intranasal administration for the potential treatment of allergic rhinitis associated nasal congestion, were identified. Compound 18b had slightly lower H1 potency (pA2 8.8 vs 9.7 for the clinical goldstandard azelastine), and H3 potency (pKi 9.1vs 6.8 for azelastine), better selectivity over α1A, α1B and hERG, similar duration of action, making 18b a good back-up compound to our previous candidate, but with a more desirable profile.
Asunto(s)
Descubrimiento de Drogas , Antagonistas de los Receptores Histamínicos H1/farmacología , Antagonistas de los Receptores Histamínicos H3/farmacología , Quinolinas/farmacología , Receptores Histamínicos H1/metabolismo , Receptores Histamínicos H3/metabolismo , Relación Dosis-Respuesta a Droga , Antagonistas de los Receptores Histamínicos H1/síntesis química , Antagonistas de los Receptores Histamínicos H1/química , Antagonistas de los Receptores Histamínicos H3/síntesis química , Antagonistas de los Receptores Histamínicos H3/química , Humanos , Ligandos , Estructura Molecular , Quinolinas/síntesis química , Quinolinas/química , Relación Estructura-ActividadRESUMEN
A series of 3-aryl((S)-3-fluoropyrrolidin-1-yl)butanoic acids were developed as potent orally bioavailable αvß6 integrin inhibitors. Starting from a zwitterionic peptidomimetic series optimized for inhaled administration, the balancing of potency and passive permeability to achieve suitable oral agents through modification and exploration of aryl substituents and pKa of the central cyclic amine is described. (S)-4-((S)-3-Fluoro-3-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethyl)pyrrolidin-1-yl)-3-(3-(2-methoxyethoxy)phenyl)butanoic acid was found to have highly desirable oral pharmacokinetic profiles in rat, dog, and minipig, with low to moderate clearance (26%, 7%, and 18% liver blood flow, respectively), moderate volumes of distribution (3.6, 1.4, and 0.9 L/kg, respectively), high to complete oral bioavailabilities, high αvß6 integrin potency of pIC50 of 8.0, and high solubility in physiological media (>2 mg/mL). Equating to the estimated human dose range of 10-75 mg b.i.d. to achieve 90% αvß6 target engagement at Cmin, it was selected for further investigation as a potential therapeutic agent for the treatment of idiopathic pulmonary fibrosis.
Asunto(s)
Antígenos de Neoplasias , Disponibilidad Biológica , Integrinas , Animales , Integrinas/antagonistas & inhibidores , Integrinas/metabolismo , Perros , Ratas , Administración Oral , Humanos , Porcinos , Antígenos de Neoplasias/metabolismo , Relación Estructura-Actividad , Descubrimiento de Drogas , Porcinos Enanos , Masculino , Ratas Sprague-DawleyRESUMEN
A series of 3-aryl(pyrrolidin-1-yl)butanoic acids were synthesized using a diastereoselective route, via a rhodium catalyzed asymmetric 1,4-addition of arylboronic acids in the presence of ( R)-BINAP to a crotonate ester to provide the ( S) absolute configuration for the major product. A variety of aryl substituents including morpholine, pyrazole, triazole, imidazole, and cyclic ether were screened in cell adhesion assays for affinity against αvß1, αvß3, αvß5, αvß6, and αvß8 integrins. Numerous analogs with high affinity and selectivity for the αvß6 integrin were identified. The analog ( S)-3-(3-(3,5-dimethyl-1 H-pyrazol-1-yl)phenyl)-4-(( R)-3-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethyl)pyrrolidin-1-yl)butanoic acid hydrochloride salt was found to have very high affinity for αvß6 integrin in a radioligand binding assay (p Ki = 11), a long dissociation half-life (7 h), very high solubility in saline at pH 7 (>71 mg/mL), and pharmacokinetic properties commensurate with inhaled dosing by nebulization. It was selected for further clinical investigation as a potential therapeutic agent for the treatment of idiopathic pulmonary fibrosis.
Asunto(s)
Descubrimiento de Drogas , Fibrosis Pulmonar Idiopática/tratamiento farmacológico , Integrinas/antagonistas & inhibidores , Pulmón/efectos de los fármacos , Pirazoles/química , Animales , Antígenos de Neoplasias , Adhesión Celular , Perros , Humanos , Pulmón/metabolismo , Masculino , Ratones , Modelos Moleculares , Estructura Molecular , Conformación Proteica , Ratas , Ratas Wistar , Relación Estructura-Actividad , Distribución TisularRESUMEN
A series of indazole arylsulfonamides were synthesized and examined as human CCR4 antagonists. Methoxy- or hydroxyl-containing groups were the more potent indazole C4 substituents. Only small groups were tolerated at C5, C6, or C7, with the C6 analogues being preferred. The most potent N3-substituent was 5-chlorothiophene-2-sulfonamide. N1 meta-substituted benzyl groups possessing an α-amino-3-[(methylamino)acyl]-group were the most potent N1-substituents. Strongly basic amino groups had low oral absorption in vivo. Less basic analogues, such as morpholines, had good oral absorption; however, they also had high clearance. The most potent compound with high absorption in two species was analogue 6 (GSK2239633A), which was selected for further development. Aryl sulfonamide antagonists bind to CCR4 at an intracellular allosteric site denoted site II. X-ray diffraction studies on two indazole sulfonamide fragments suggested the presence of an important intramolecular interaction in the active conformation.
Asunto(s)
Indazoles/farmacología , Receptores CCR4/antagonistas & inhibidores , Sulfonamidas/síntesis química , Sulfonamidas/farmacología , Animales , Perros , Humanos , Indazoles/síntesis química , Indazoles/farmacocinética , Masculino , Ratas , Relación Estructura-Actividad , Sulfonamidas/farmacocinéticaRESUMEN
A series of potent phthalazinone-based human H(1) and H(3) bivalent histamine receptor antagonists, suitable for intranasal administration for the potential treatment of allergic rhinitis, were identified. Blockade of H(3) receptors is thought to improve efficacy on nasal congestion, a symptom of allergic rhinitis that is currently not treated by current antihistamines. Two analogues (56a and 56b) had slightly lower H(1) potency (pA(2) 9.1 and 8.9, respectively, vs 9.7 for the clinical gold-standard azelastine, and H(3) potency (pK(i) 9.6 and 9.5, respectively, vs 6.8 for azelastine). Compound 56a had longer duration of action than azelastine, low brain penetration, and low oral bioavailability, which coupled with the predicted low clinical dose, should limit the potential of engaging CNS-related side-effects associated with H(1) or H(3) antagonism.
Asunto(s)
Descubrimiento de Drogas/métodos , Ftalazinas/administración & dosificación , Ftalazinas/farmacología , Receptores Histamínicos H1/metabolismo , Receptores Histamínicos H3/metabolismo , Rinitis/tratamiento farmacológico , Administración Intranasal , Administración Oral , Antagonistas de los Receptores Histamínicos H1/administración & dosificación , Antagonistas de los Receptores Histamínicos H1/química , Antagonistas de los Receptores Histamínicos H1/farmacología , Antagonistas de los Receptores Histamínicos H1/uso terapéutico , Antagonistas de los Receptores Histamínicos H3/administración & dosificación , Antagonistas de los Receptores Histamínicos H3/química , Antagonistas de los Receptores Histamínicos H3/farmacología , Antagonistas de los Receptores Histamínicos H3/uso terapéutico , Humanos , Modelos Moleculares , Ftalazinas/química , Ftalazinas/uso terapéutico , Conformación Proteica , Receptores Histamínicos H1/químicaRESUMEN
High-throughput screening of the corporate compound collection led to the discovery of a novel series of N-substituted-5-aryl-oxazolidinones as potent human CCR8 antagonists. The synthesis, structure-activity relationships, and optimization of the series that led to the identification of SB-649701 (1a), are described.