RESUMEN
Starting from acylsufonamide HTS hit 2, a novel series of para-N-acylaminomethylbenzoic acids was identified and developed as selective prostaglandin EP4 receptor antagonists. Structural modifications on lead compound 4a were explored with the aim of improving potency, physicochemical properties, and animal PK predictive of QD (once a day) dosing regimen in human. These efforts led to the discovery of the clinical candidate AAT-008 (4j), which exhibited significantly improved pharmacological profiles over grapiprant (1).
Asunto(s)
Benzoatos/farmacología , Niacinamida/análogos & derivados , Antagonistas de Prostaglandina/farmacología , Subtipo EP4 de Receptores de Prostaglandina E/antagonistas & inhibidores , Animales , Benzoatos/química , Benzoatos/farmacocinética , Descubrimiento de Drogas , Humanos , Niacinamida/química , Niacinamida/farmacocinética , Niacinamida/farmacología , Antagonistas de Prostaglandina/química , Antagonistas de Prostaglandina/farmacocinética , Relación Estructura-ActividadRESUMEN
A novel series of pyrrolopyrazole-based protein kinase C ß II inhibitors has been identified from high-throughput screening. Herein, we report our initial structure-activity relationship studies with a focus on optimizing compound ligand efficiency and physicochemical properties, which has led to potent inhibitors with good cell permeability.
Asunto(s)
Proteína Quinasa C/antagonistas & inhibidores , Inhibidores de Proteínas Quinasas/química , Pirazoles/química , Ensayos Analíticos de Alto Rendimiento , Proteína Quinasa C/metabolismo , Proteína Quinasa C beta , Inhibidores de Proteínas Quinasas/síntesis química , Inhibidores de Proteínas Quinasas/farmacología , Pirazoles/síntesis química , Pirazoles/farmacología , Relación Estructura-ActividadRESUMEN
A novel series of potent thioether benzenesulfonamide inhibitors of carbonic anhydrases II and IV was discovered using structure-based drug design. Synthesis, structure-activity relationship, and optimization of physicochemical properties are described. Low nanomolar potency was achieved, and selected compounds with improved thermodynamic solubility showed promising in vitro inhibition of carbonic anhydrase activity in rabbit iris ciliary body homogenate.
Asunto(s)
Anhidrasa Carbónica II/antagonistas & inhibidores , Inhibidores de Anhidrasa Carbónica , Diseño de Fármacos , Animales , Anhidrasa Carbónica II/química , Inhibidores de Anhidrasa Carbónica/síntesis química , Inhibidores de Anhidrasa Carbónica/química , Inhibidores de Anhidrasa Carbónica/farmacología , Cristalografía por Rayos X , Humanos , Conejos , Relación Estructura-Actividad , Sulfuros/síntesis química , Sulfuros/química , Sulfuros/farmacología , Sulfonamidas/síntesis química , Sulfonamidas/química , Sulfonamidas/farmacología , BencenosulfonamidasRESUMEN
Protein kinase C (PKC) family members such as PKCbetaII may become activated in the hyperglycemic state associated with diabetes. Preclinical and clinical data implicate aberrant PKC activity in the development of diabetic microvasculature abnormalities. Based on this potential etiological role for PKC in diabetic complications, several therapeutic PKC inhibitors have been investigated in clinical trials for the treatment of diabetic patients. In this report, we present the discovery and preclinical evaluation of a novel class of 3-amino-pyrrolo[3,4-c]pyrazole derivatives as inhibitors of PKC that are structurally distinct from the prototypical indolocarbazole and bisindolylmaleimide PKC inhibitors. From this pyrrolo-pyrazole series, several compounds were identified from biochemical assays as potent, ATP-competitive inhibitors of PKC activity with high specificity for PKC over other protein kinases. These compounds were also found to block PKC signaling activity in multiple cellular functional assays. PF-04577806, a representative from this series, inhibited PKC activity in retinal lysates from diabetic rats stimulated with phorbol myristate acetate. When orally administered, PF-04577806 showed good exposure in the retina of diabetic Long-Evans rats and ameliorated retinal vascular leakage in a streptozotocin-induced diabetic rat model. These novel PKC inhibitors represent a promising new class of targeted protein kinase inhibitors with potential as therapeutic agents for the treatment of patients with diabetic microvascular complications.
Asunto(s)
Complicaciones de la Diabetes/metabolismo , Descubrimiento de Drogas , Proteína Quinasa C/antagonistas & inhibidores , Inhibidores de Proteínas Quinasas/farmacología , Enfermedades de la Retina/metabolismo , Vasos Retinianos/efectos de los fármacos , Transducción de Señal/efectos de los fármacos , Administración Oral , Animales , Bovinos , Línea Celular , Complicaciones de la Diabetes/tratamiento farmacológico , Complicaciones de la Diabetes/enzimología , Modelos Animales de Enfermedad , Humanos , Masculino , Proteína Quinasa C/metabolismo , Inhibidores de Proteínas Quinasas/administración & dosificación , Inhibidores de Proteínas Quinasas/química , Inhibidores de Proteínas Quinasas/farmacocinética , Pirazoles/administración & dosificación , Pirazoles/química , Pirazoles/farmacocinética , Pirazoles/farmacología , Ratas , Enfermedades de la Retina/tratamiento farmacológico , Enfermedades de la Retina/enzimología , Vasos Retinianos/metabolismo , Vasos Retinianos/patología , Especificidad por SustratoRESUMEN
The title compound, C(9)H(7)ClN(2)O(2), was prepared by reaction of methyl 4-chloro-3-(prop-1-yn-yl)picolinate with hydroxy-l-amine in MeOH/KOH solution. The two essentially planar mol-ecules which make up the asymmetric unit have almost identical geometries and and are linked into dimeric aggregates via pairs of O-Hâ¯O hydrogen bonds. These aggregates have almost perfect inversion symmetry; however, quite unusually, the inversion center of the dimer does not coincide with the crystallographic inversion center.
RESUMEN
In the title compound, C(15)H(14)N(4), the pyrido[2,3-d]pyrimidine system is almost ideally planar (r.m.s. deviation 0.028â Å) with its mean plane almost orthogonal to the 2,6-dimethyl-phenyl plane. The dihedral angle formed by these planes [87.3â (2)°] is close to the predicted value (89.7°) obtained by mol-ecular-mechanics force-field calculations. Only one of the two active amine H atoms participates in hydrogen bonding, which links mol-ecules into centrosymmetric dimers.
RESUMEN
A novel central nervous system (CNS) selective neurokinin-1 (NK(1)) receptor antagonist, (2S,3S)-3-[(1R)-6-methoxy-1-methyl-1-trifluoromethylisochroman-7-yl]-methylamino-2-phenylpiperidine 'CJ-17,493' (compound (+)-1), was synthesized stereoselectively using a kinetic resolution by lipase-PS as a key step. Compound (+)-1 displayed high and selective affinity (K(i)=0.2 nM) for the human NK(1) receptor in IM-9 cells, potent activity in the [Sar(9), Met(O(2))(11)]SP-induced gerbil tapping model (ED(50)=0.04 mg/kg, s.c.) and in the ferret cisplatin (10mg/kg, i.p.)-induced anti-emetic activity model (vomiting: ED(90)=0.07 mg/kg, s.c.), all levels of activity comparable with those of CP-122,721. In addition, compound (+)-1 exhibited linear pharmacokinetics rather than the super dose-proportionality of CP-122,721 and this result provides a potential solution for the clinical issue observed with CP-122,721.
Asunto(s)
Benzopiranos/química , Benzopiranos/farmacología , Antagonistas del Receptor de Neuroquinina-1 , Piperidinas/química , Piperidinas/farmacología , Animales , Antieméticos/química , Antieméticos/farmacología , Línea Celular , Cisplatino/toxicidad , Relación Dosis-Respuesta a Droga , Hurones , Gerbillinae , Humanos , Estructura Molecular , Relación Estructura-Actividad , Vómitos/inducido químicamente , Vómitos/tratamiento farmacológicoRESUMEN
The reaction of 3-amino-5-bromo-pyridine with N-iodo-succinimide in the presence of acetic acid produces the title compound, C(5)H(4)BrIN, with an iodo substituent in position 2 of the pyridine ring. The crystal structure features rather weak inter-molecular N-Hâ¯N hydrogen bonds linking the mol-ecules into chains along the z axis of the crystal.
RESUMEN
Novel NR2B antagonists with an amide tether were found by an approach to avoid pharmacophoric similarity to dofetilide. Structure-activity relationship investigation led to N-[cis-4-hydroxy-4-(5-hydroxypyridin-2-yl)cyclohexyl]-3-henylpropanamide as an orally active NR2B-subtype selective N-methyl-D-aspartate (NMDA) receptor antagonist with very weak HERG (human ether-a-go-go related gene) binding (IC(50)> 30 microM). This compound exhibited potent in vivo anti-allodynic activity in the mouse partial sciatic nerve ligation (PSL) model (minimum effective dose=10 mg/kg, po).
Asunto(s)
Diseño de Fármacos , Canales de Potasio Éter-A-Go-Go/metabolismo , N-Metilaspartato/antagonistas & inhibidores , N-Metilaspartato/metabolismo , Piridinas/química , Piridinas/farmacología , Receptores de N-Metil-D-Aspartato/metabolismo , Administración Oral , Concentración 50 Inhibidora , Estructura Molecular , N-Metilaspartato/administración & dosificación , Piridinas/síntesis química , Solubilidad , Relación Estructura-ActividadRESUMEN
Full details of the synthesis of (9R,12S)- and (9S,12S)-cycloisodityrosine and their N-methyl derivatives are detailed based on an intramolecular nucleophilic aromatic substitution reaction for formation of the key biaryl ether with 14-membered ring macrocyclization. Their comparison with prior samples and the documentation of a facile C9 epimerization within the natural 9S series are described.