RESUMEN
A practical synthesis of capromorelin (1), a growth hormone secretagogue, is described that utilizes as a key step a crystallization-induced dynamic resolution (CIDR) of (±)-3a-benzyl-2-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridin-3(3aH)-one [(±)-2] by L-tartaric acid salt formation, yielding (R)-2.L-tartaric acid in high chemical yield (>85%) and with diastereomeric excess (de) of â¼98%. Treatment of (R)-2.L-tartaric acid with ammonium hydroxide provided (R)-2 without loss of chiral purity. In situ generated (R)-2 was coupled with (R)-3-(benzyloxy)-2-(2-(tert-butoxycarbonyl)-2-methylpropanamido)propanoic acid [(R)-3] to give predominantly a single diastereomer of N-Boc-protected capromorelin [(1R,3aR)-4]. This process was used to prepare bulk quantities of capromorelin from (±)-2 to support preclinical toxicology studies.
Asunto(s)
Piperidinas/síntesis química , Pirazoles/síntesis química , Termodinámica , Cristalografía por Rayos X , Modelos Moleculares , Estructura Molecular , Piperidinas/química , Pirazoles/químicaRESUMEN
Previous drug discovery efforts identified classical PYK2 kinase inhibitors such as 2 and 3 that possess selectivity for PYK2 over its intra-family isoform FAK. Efforts to identify more kinome-selective chemical matter that stabilize a DFG-out conformation of the enzyme are described herein. Two sub-series of PYK2 inhibitors, an indole carboxamide-urea and a pyrazole-urea have been identified and found to have different binding interactions with the hinge region of PYK2. These leads proved to be more selective than the original classical inhibitors.
Asunto(s)
Quinasa 2 de Adhesión Focal/antagonistas & inhibidores , Indoles/farmacología , Inhibidores de Proteínas Quinasas/farmacología , Pirazoles/farmacología , Urea/farmacología , Animales , Cristalografía por Rayos X , Relación Dosis-Respuesta a Droga , Quinasa 2 de Adhesión Focal/metabolismo , Células HEK293 , Humanos , Indoles/síntesis química , Indoles/química , Modelos Moleculares , Estructura Molecular , Inhibidores de Proteínas Quinasas/síntesis química , Inhibidores de Proteínas Quinasas/química , Pirazoles/síntesis química , Pirazoles/química , Ratas , Relación Estructura-Actividad , Urea/análogos & derivados , Urea/químicaRESUMEN
Previous studies have demonstrated the CYP3A4 mediated oxidation of the 5-aminooxindole motif, present in the trifluoromethylpyrimidine class of PYK-2 inhibitors, to a reactive bis-imine species, which can be trapped with glutathione (GSH) in human liver microsomal incubations. The corresponding 5-aminobenzsultam derivatives, which should possess a similar oxidative liability, do not form GSH conjugates in microsomal incubations. In the current study, we conducted a retrospective analysis on representative 5-aminooxindole and 5-aminobenzsultam PYK-2 inhibitors utilizing CYP3A4 molecular docking and quantum chemical calculations to rationalize the bioactivation differences. Our analysis revealed key differences in (a) active site binding and (b) two-electron oxidation rates, which correlate with GSH adduct formation with the two moieties. The value of linear ion/orbitrap mass spectrometry to detect GSH conjugates with greater sensitivity, compared with conventional triple quadrupole mass spectrometry approaches, was also demonstrated in the course of these studies.
Asunto(s)
Derivados del Benceno/farmacología , Citocromo P-450 CYP3A/metabolismo , Quinasa 2 de Adhesión Focal/antagonistas & inhibidores , Glutatión/metabolismo , Indoles/farmacología , Aminas/farmacología , Catálisis , Simulación por Computador , Humanos , Espectrometría de Masas , Microsomas , Modelos Moleculares , Oxidación-Reducción , Oxindoles , Unión Proteica , Inhibidores de Proteínas QuinasasRESUMEN
Sulfonamides, exemplified by 3a, were identified as highly selective EP(2) agonists. Lead optimization led to the identification of CP-533536, 7f, a potent and selective EP(2) agonist. CP-533536 demonstrated the ability to heal fractures when administered locally as a single dose in rat models of fracture healing.
Asunto(s)
Osteogénesis/efectos de los fármacos , Piridinas/química , Receptores de Prostaglandina E/agonistas , Animales , Masculino , Piridinas/administración & dosificación , Piridinas/farmacocinética , Ratas , Ratas Sprague-Dawley , Receptores de Prostaglandina E/metabolismo , Subtipo EP2 de Receptores de Prostaglandina E , Relación Estructura-Actividad , Sulfonamidas/síntesis química , Sulfonamidas/química , Sulfonamidas/farmacologíaRESUMEN
The synthesis, in vitro properties, and in vivo pharmacokinetics for a series of sulfoximine-substituted trifluoromethylpyrimidines as inhibitors of proline-rich tyrosine kinase, a target for the possible treatment of osteoporosis, are described. These compounds were prepared as surrogates of the corresponding sulfone compound 1. Sulfone 1 was an attractive PYK2 lead compound; however, subsequent studies determined this compound possessed high dofetilide binding, which is an early indicator of cardiovascular safety. Surprisingly, the corresponding sulfoximine analogs displayed significantly lower dofetilide binding, which, for N-methylsulfoximine (S)-14a, translated to lower activity in a patch clamp hERG K(+) ion channel screen. In addition, compound (S)-14a shows good oral exposure in a rat pharmacokinetic model.
Asunto(s)
Canales de Potasio Éter-A-Go-Go/metabolismo , Quinasa 2 de Adhesión Focal/antagonistas & inhibidores , Pirimidinas/química , Pirimidinas/farmacología , Administración Oral , Animales , Evaluación Preclínica de Medicamentos , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/farmacocinética , Inhibidores Enzimáticos/farmacología , Humanos , Iminas/química , Osteoporosis/tratamiento farmacológico , Técnicas de Placa-Clamp , Fenetilaminas , Pirimidinas/farmacocinética , Ratas , Relación Estructura-Actividad , Sulfonamidas , Sulfonas/químicaRESUMEN
Synthesis and structure-activity relationship (SAR) studies on 5-trifluoromethylpyrido[4,3-d]pyrimidin-4(3H)-ones, a novel class of calcium receptor antagonists is described with particular emphasis on optimization of the pharmacokinetic/pharmacodynamic parameters required for a short duration of action compound. Orally-active compounds were identified which displayed the desired animal pharmacology (rapid and transient stimulation of parathyroid hormone) essential for bone anabolic effects.
Asunto(s)
Anabolizantes/química , Pirimidinonas/química , Receptores Sensibles al Calcio/antagonistas & inhibidores , Administración Oral , Anabolizantes/administración & dosificación , Anabolizantes/farmacocinética , Animales , Masculino , Hormona Paratiroidea/metabolismo , Pirimidinonas/administración & dosificación , Pirimidinonas/farmacocinética , Ratas , Ratas Sprague-Dawley , Receptores Sensibles al Calcio/metabolismo , Relación Estructura-ActividadRESUMEN
The synthesis and SAR for a series of diaminopyrimidines as PYK2 inhibitors are described. Using a combination of library and traditional medicinal chemistry techniques, a FAK-selective chemical series was transformed into compounds possessing good PYK2 potency and 10- to 20-fold selectivity against FAK. Subsequent studies found that the majority of the compounds were positive in a reactive metabolite assay, an indicator for potential toxicological liabilities. Based on the proposed mechanism for bioactivation, as well as a combination of structure-based drug design and traditional medicinal chemistry techniques, a follow-up series of PYK2 inhibitors was identified that maintained PYK2 potency, FAK selectivity and HLM stability, yet were negative in the RM assay.
Asunto(s)
Quinasa 2 de Adhesión Focal/antagonistas & inhibidores , Pirimidinas/síntesis química , Pirimidinas/farmacología , Animales , Técnicas Químicas Combinatorias , Cristalografía por Rayos X , Modelos Animales de Enfermedad , Diseño de Fármacos , Proteína-Tirosina Quinasas de Adhesión Focal/antagonistas & inhibidores , Humanos , Conformación Molecular , Estructura Molecular , Osteoporosis/tratamiento farmacológico , Pirimidinas/química , Ratas , Relación Estructura-ActividadRESUMEN
Heptanoic acid lactams, exemplified by 2, were identified as highly selective EP4 agonists via high throughput screening. Lead optimization led to the identification of lactams with a 30-fold increase in EP4 potency in vitro. Compounds demonstrated robust bone anabolic effects when administered in vivo in rat models of osteoporosis.
Asunto(s)
Densidad Ósea/efectos de los fármacos , Desarrollo Óseo , Huesos/efectos de los fármacos , Tamaño de los Órganos/efectos de los fármacos , Ovariectomía , Receptores de Prostaglandina E/agonistas , Animales , Femenino , Osteoporosis , Ratas , Ratas Sprague-Dawley , Subtipo EP4 de Receptores de Prostaglandina ERESUMEN
Two series of 6-hydroxy and 7-hydroxy tetrahydroisoquinolines were prepared. Evaluating a range of C-1, C-4, and N-substituents led to the discovery of ER alpha and ER beta selective analogs.
Asunto(s)
Moduladores Selectivos de los Receptores de Estrógeno/síntesis química , Tetrahidroisoquinolinas/farmacología , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Receptor alfa de Estrógeno/química , Receptor beta de Estrógeno/química , Femenino , Humanos , Concentración 50 Inhibidora , Ligandos , Unión Proteica , Moduladores Selectivos de los Receptores de Estrógeno/farmacología , Relación Estructura-Actividad , Tetrahidroisoquinolinas/síntesis químicaRESUMEN
Novel pyrazolinone-piperidine dipeptide derivatives were synthesized and evaluated as growth hormone secretagogues (GHSs). Two analogues, capromorelin (5, CP-424391-18, hGHS-R1a K(i)=7 nM, rat pituicyte EC(50)=3 nM) and the des-methyl analogue 5c (hGHS-R1a K(i)=17 nM, rat pituicyte EC(50)=3 nM), increased plasma GH levels in an anesthesized rat model, with ED(50) values less than 0.05 mg/kg iv. Capromorelin showed enhanced intestinal absorption in rodent models and exhibited superior pharmacokinetic properties, including high bioavailabilities in two animal species [F(rat)=65%, F(dog)=44%]. This short-duration GHS was orally active in canine models and was selected as a development candidate for the treatment of musculoskeletal frailty in elderly adults.
Asunto(s)
Dipéptidos/síntesis química , Dipéptidos/farmacología , Hormona del Crecimiento/metabolismo , Piperidinas/síntesis química , Piperidinas/farmacología , Pirazoles/síntesis química , Pirazoles/farmacología , Animales , Células Cultivadas , Fenómenos Químicos , Química Física , ADN Complementario/metabolismo , Dipéptidos/farmacocinética , Perros , Diseño de Fármacos , Femenino , Semivida , Humanos , Indicadores y Reactivos , Indoles/farmacología , Espectroscopía de Resonancia Magnética , Piperidinas/farmacocinética , Hipófisis/citología , Hipófisis/efectos de los fármacos , Hipófisis/metabolismo , Pirazoles/farmacocinética , Ratas , Ratas Sprague-Dawley , Ratas Wistar , Solubilidad , Compuestos de Espiro/farmacologíaRESUMEN
New tert-butyl, picolyl and fluorinated analogues of capromorelin (3), a short-acting growth hormone secretagogue (GHS), were prepared as part of a program to identify long-acting GHSs that increase 24-h plasma IGF-1 levels. Compounds 4c and 4d (ACD LogD values >or=2.9) displayed extended plasma elimination half-lives in dogs, primarily due to high volumes of distribution, but showed weak GH secretagogue activities in rats (ED(50)s>10 mg/kg). A less lipophilic derivative 4 (ACD LogD=1.6) exhibited a shorter canine half-life, but stimulated GH secretion in two animal species. Repeat oral dosing of 4 in dogs for 29 days (6 mg/kg) resulted in a significant down-regulation of the post dose GH response and a 60 and 40% increase in IGF-1 levels relative to pre-dose levels at the 8- and 24-h post dose time points. Compound 4 (CP-464709-18) has been selected as a development candidate for the treatment of frailty.