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1.
J Immunol ; 197(6): 2421-33, 2016 09 15.
Artículo en Inglés | MEDLINE | ID: mdl-27521339

RESUMEN

A critical component of innate immune response to infection and tissue damage is the NACHT, LRR, and PYD domains-containing protein 3 (NLRP3) inflammasome, and this pathway and its activation products have been implicated in the pathophysiology of a variety of diseases. NLRP3 inflammasome activation leads to the cleavage of pro-IL-1ß and pro-IL-18, as well as the subsequent release of biologically active IL-1ß, IL-18, and other soluble mediators of inflammation. In this study, we further define the pharmacology of the previously reported NLRP3 inflammasome-selective, IL-1ß processing inhibitor CP-456,773 (also known as MCC950), and we demonstrate its efficacy in two in vivo models of inflammation. Specifically, we show that in human and mouse innate immune cells CP-456,773 is an inhibitor of the cellular release of IL-1ß, IL-1α, and IL-18, that CP-456,773 prevents inflammasome activation induced by disease-relevant soluble and crystalline NLRP3 stimuli, and that CP-456,773 inhibits R848- and imiquimod-induced IL-1ß release. In mice, CP-456,773 demonstrates potent inhibition of the release of proinflammatory cytokines following acute i.p. challenge with LPS plus ATP in a manner that is proportional to the free/unbound concentrations of the drug, thereby establishing an in vivo pharmacokinetic/pharmacodynamic model for CP-456,773. Furthermore, CP-456,773 reduces ear swelling in an imiquimod cream-induced mouse model of skin inflammation, and it reduces airway inflammation in mice following acute challenge with house dust mite extract. These data implicate the NLRP3 inflammasome in the pathogenesis of dermal and airway inflammation, and they highlight the utility of CP-456,773 for interrogating the contribution of the NLRP3 inflammasome and its outputs in preclinical models of inflammation and disease.


Asunto(s)
Dermatitis/tratamiento farmacológico , Compuestos Heterocíclicos de 4 o más Anillos/farmacología , Inflamasomas/antagonistas & inhibidores , Inflamación/fisiopatología , Proteína con Dominio Pirina 3 de la Familia NLR/antagonistas & inhibidores , Neumonía/tratamiento farmacológico , Neumonía/inmunología , Sulfonas/farmacología , Animales , Citocinas/antagonistas & inhibidores , Citocinas/inmunología , Dermatitis/inmunología , Dermatitis/fisiopatología , Modelos Animales de Enfermedad , Furanos , Compuestos Heterocíclicos de 4 o más Anillos/administración & dosificación , Compuestos Heterocíclicos de 4 o más Anillos/uso terapéutico , Humanos , Inmunidad Innata/efectos de los fármacos , Indenos , Inflamación/tratamiento farmacológico , Inflamación/inmunología , Interleucina-18/antagonistas & inhibidores , Interleucina-18/metabolismo , Interleucina-1alfa/antagonistas & inhibidores , Interleucina-1alfa/metabolismo , Interleucina-1beta/antagonistas & inhibidores , Interleucina-1beta/inmunología , Ratones , Neumonía/fisiopatología , Transducción de Señal , Sulfonamidas , Sulfonas/administración & dosificación , Sulfonas/uso terapéutico
2.
Bioorg Med Chem ; 25(3): 1000-1003, 2017 02 01.
Artículo en Inglés | MEDLINE | ID: mdl-28012686

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 ∼98%. 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/química
3.
Angew Chem Int Ed Engl ; 55(33): 9601-5, 2016 08 08.
Artículo en Inglés | MEDLINE | ID: mdl-27355874

RESUMEN

Glycogen synthase kinase-3 (GSK-3) regulates multiple cellular processes in diabetes, oncology, and neurology. N-(3-(1H-1,2,4-triazol-1-yl)propyl)-5-(3-chloro-4-methoxyphenyl)oxazole-4-carboxamide (PF-04802367 or PF-367) has been identified as a highly potent inhibitor, which is among the most selective antagonists of GSK-3 to date. Its efficacy was demonstrated in modulation of tau phosphorylation in vitro and in vivo. Whereas the kinetics of PF-367 binding in brain tissues are too fast for an effective therapeutic agent, the pharmacokinetic profile of PF-367 is ideal for discovery of radiopharmaceuticals for GSK-3 in the central nervous system. A (11) C-isotopologue of PF-367 was synthesized and preliminary PET imaging studies in non-human primates confirmed that we have overcome the two major obstacles for imaging GSK-3, namely, reasonable brain permeability and displaceable binding.


Asunto(s)
Encéfalo/efectos de los fármacos , Encéfalo/diagnóstico por imagen , Neuroimagen , Oxazoles/farmacología , Tomografía de Emisión de Positrones , Inhibidores de Proteínas Quinasas/farmacología , Triazoles/farmacología , Proteínas tau/antagonistas & inhibidores , Encéfalo/metabolismo , Cristalografía por Rayos X , Relación Dosis-Respuesta a Droga , Glucógeno Sintasa Quinasa 3/antagonistas & inhibidores , Glucógeno Sintasa Quinasa 3/metabolismo , Humanos , Modelos Moleculares , Estructura Molecular , Oxazoles/síntesis química , Oxazoles/química , Fosforilación/efectos de los fármacos , Inhibidores de Proteínas Quinasas/síntesis química , Inhibidores de Proteínas Quinasas/química , Triazoles/síntesis química , Triazoles/química , Proteínas tau/metabolismo
4.
Xenobiotica ; 44(7): 591-605, 2014 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-24380613

RESUMEN

1. Elaborate studies of cholesteryl ester transfer protein (CETP) polymorphisms and genetic deficiency in humans suggest direct links between CETP, high-density lipoprotein cholesterol (HDL-c) levels and coronary heart diseases. The hypothesis that CETP inhibition by small molecule inhibitors raises HDL-c has been validated clinically with structurally-diverse CETP inhibitors such as torcetrapib, anacetrapib, dalcetrapib and evacetrapib. 2. Despite promising phase 2 results with respect to HDL-c elevation, torcetrapib was discontinued in phase 3 trials due to increased mortality rates in the cardiovascular outcomes study. Emerging evidence for the adverse effects hints at off-target chemotype-specific cardiovascular toxicity, possibly related to the pressor effects of torcetrapib, since structurally diverse CETP inhibitors such as anacetrapib, evacetrapib and dalcetrapib are not associated with blood pressure increases in humans. Nonclinical follow-up studies showed that torcetrapib induces aldosterone biosynthesis and secretion in vivo and in vitro, an effect which is not observed with other CETP inhibitors in clinical development. 3. As part of ongoing efforts to identify novel CETP inhibitors devoid of pressor effects, strategies were implemented towards the design of compounds, which lack the 1,2,3,4-tetrahydroquinoline (THQ) scaffold present in torcetrapib. In this article, we disclose results of structure-activity relationship studies for a series of novel non-THQ CETP inhibitors, which resulted in the identification of a novel isonipecotic acid derivative 10 (also referred to as PF-04445597) with vastly improved oral pharmacokinetic properties mainly as a result of improved aqueous solubility. This feature is attractive in that, it bypasses significant investments needed to develop compatible solubilizing formulation(s) for oral drug delivery of highly lipophilic and poorly soluble compounds; attributes, which are usually associated with small molecule CETP inhibitors. PF-04445597 was also devoid of aldosterone secretion in human H295R adrenal carcinoma cells.


Asunto(s)
Anticolesterolemiantes/química , Anticolesterolemiantes/farmacología , Proteínas de Transferencia de Ésteres de Colesterol/antagonistas & inhibidores , Evaluación Preclínica de Medicamentos/métodos , Quinolinas/química , Administración Oral , Aldosterona/metabolismo , Animales , Anticolesterolemiantes/farmacocinética , Inhibidores del Citocromo P-450 CYP3A/química , Inhibidores del Citocromo P-450 CYP3A/farmacología , Diseño de Fármacos , Femenino , Humanos , Inyecciones Intravenosas , Ácidos Isonipecóticos/química , Ácidos Isonipecóticos/farmacología , Macaca fascicularis , Masculino , Microsomas Hepáticos/efectos de los fármacos , Microsomas Hepáticos/metabolismo , Quinolinas/farmacología , Ratas Sprague-Dawley , Solubilidad , Relación Estructura-Actividad
5.
Bioorg Med Chem Lett ; 23(1): 194-7, 2013 Jan 01.
Artículo en Inglés | MEDLINE | ID: mdl-23177788

RESUMEN

A novel GPR119 agonist based on the 2,4,5,6-tetrahydropyrrolo[3,4-c]pyrazole scaffold was designed through lead optimization starting from pyrazole-based GPR119 agonist 1. The design is centered on the conformational restriction of the core scaffold, while minimizing the change in spatial relationships of two key pharmacophoric elements (piperidine-carbamate and aryl sulfone).


Asunto(s)
Pirazoles/química , Receptores Acoplados a Proteínas G/agonistas , Carbamatos/química , Humanos , Piperidinas/química , Unión Proteica , Pirazoles/síntesis química , Pirazoles/metabolismo , Receptores Acoplados a Proteínas G/metabolismo , Relación Estructura-Actividad
6.
Bioorg Med Chem Lett ; 21(5): 1306-9, 2011 Mar 01.
Artículo en Inglés | MEDLINE | ID: mdl-21310611

RESUMEN

The design and synthesis of a GPR119 agonist bearing a 2-(2,3,6-trifluorophenyl)acetamide group is described. The design capitalized on the conformational restriction found in N-ß-fluoroethylamide derivatives to help maintain good levels of potency while driving down both lipophilicity and oxidative metabolism in human liver microsomes. The chemical stability and bioactivation potential are discussed.


Asunto(s)
Acetamidas/química , Acetamidas/farmacología , Diseño de Fármacos , Receptores Acoplados a Proteínas G/agonistas , Acetamidas/síntesis química , Humanos , Concentración 50 Inhibidora , Espectroscopía de Resonancia Magnética , Estructura Molecular , Receptores Acoplados a Proteínas G/química
8.
Bioorg Med Chem Lett ; 19(7): 2075-8, 2009 Apr 01.
Artículo en Inglés | MEDLINE | ID: mdl-19250823

RESUMEN

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/farmacología
9.
ACS Med Chem Lett ; 10(8): 1104-1109, 2019 Aug 08.
Artículo en Inglés | MEDLINE | ID: mdl-31413793

RESUMEN

Many pharmaceutical companies have invested millions of dollars in establishing internal chemical stores to provide reliable access to large numbers of building blocks (BB) for the synthesis of new molecules, especially for the timely design and execution of parallel (library) synthesis. Recognizing budget and logistical limitations, we required a more economically scalable process to provide diverse BB. We disclose a novel business partnership that achieves the goals of just-in-time, economical access to commercial BB that increases chemical space coverage and accelerates the synthesis of new drug candidates. We believe that this model can be of benefit to companies of all sizes that are engaged in drug discovery by reducing cost, increasing diversity of analog molecules in a time-conscious manner, and reducing BB inventory. More efficient use of BB by customers may allow commercial vendors to devote a greater portion of their resources to preparing novel BB that increase chemical diversity as opposed to resynthesizing out-of-stock compounds that are inaccessible within company compound collections.

10.
J Bone Miner Res ; 21(4): 565-75, 2006 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-16598377

RESUMEN

UNLABELLED: CP432 is a newly discovered, nonprostanoid EP4 receptor selective prostaglandin E2 agonist. CP432 stimulates trabecular and cortical bone formation and restores bone mass and bone strength in aged ovariectomized rats with established osteopenia. INTRODUCTION: The purpose of this study was to determine whether a newly discovered, nonprostanoid EP4 receptor selective prostaglandin E2 (PGE2) agonist, CP432, could produce bone anabolic effects in aged, ovariectomized (OVX) rats with established osteopenia. MATERIALS AND METHODS: CP432 at 0.3, 1, or 3 mg/kg/day was given for 6 weeks by subcutaneous injection to 12-month-old rats that had been OVX for 8.5 months. The effects on bone mass, bone formation, bone resorption, and bone strength were determined. RESULTS: Total femoral BMD increased significantly in OVX rats treated with CP432 at all doses. CP432 completely restored trabecular bone volume of the third lumbar vertebral body accompanied with a dose-dependent decrease in osteoclast number and osteoclast surface and a dose-dependent increase in mineralizing surface, mineral apposition rate, and bone formation rate-tissue reference in OVX rats. CP432 at 1 and 3 mg/kg/day significantly increased total tissue area, cortical bone area, and periosteal and endocortical bone formation in the tibial shafts compared with both sham and OVX controls. CP432 at all doses significantly and dose-dependently increased ultimate strength in the fifth lumber vertebral body compared with both sham and OVX controls. At 1 and 3 mg/kg/day, CP432 significantly increased maximal load in a three-point bending test of femoral shaft compared with both sham and OVX controls. CONCLUSIONS: CP432 completely restored trabecular and cortical bone mass and strength in established osteopenic, aged OVX rats by stimulating bone formation and inhibiting bone resorption on trabecular and cortical surfaces.


Asunto(s)
Envejecimiento/fisiología , Densidad Ósea/efectos de los fármacos , Enfermedades Óseas Metabólicas/tratamiento farmacológico , Dinoprostona/agonistas , Osteogénesis/efectos de los fármacos , Receptores de Prostaglandina E/agonistas , Receptores de Prostaglandina E/metabolismo , Animales , Peso Corporal , Densidad Ósea/fisiología , Modelos Animales de Enfermedad , Femenino , Fémur/anatomía & histología , Vértebras Lumbares/anatomía & histología , Estructura Molecular , Tamaño de los Órganos/efectos de los fármacos , Ovariectomía , Ratas , Ratas Sprague-Dawley , Subtipo EP4 de Receptores de Prostaglandina E , Especificidad por Sustrato , Tibia/anatomía & histología
11.
Sci Rep ; 6: 30859, 2016 08 16.
Artículo en Inglés | MEDLINE | ID: mdl-27527709

RESUMEN

Interleukin-17A (IL-17A) is a principal driver of multiple inflammatory and immune disorders. Antibodies that neutralize IL-17A or its receptor (IL-17RA) deliver efficacy in autoimmune diseases, but no small-molecule IL-17A antagonists have yet progressed into clinical trials. Investigation of a series of linear peptide ligands to IL-17A and characterization of their binding site has enabled the design of novel macrocyclic ligands that are themselves potent IL-17A antagonists.


Asunto(s)
Interleucina-17/antagonistas & inhibidores , Interleucina-17/química , Péptidos Cíclicos/farmacología , Bibliotecas de Moléculas Pequeñas/farmacología , Algoritmos , Sitios de Unión , Células Cultivadas , Diseño de Fármacos , Humanos , Queratinocitos/citología , Queratinocitos/efectos de los fármacos , Queratinocitos/metabolismo , Compuestos Macrocíclicos/química , Compuestos Macrocíclicos/farmacología , Simulación de Dinámica Molecular , Péptidos Cíclicos/química , Unión Proteica , Bibliotecas de Moléculas Pequeñas/química , Relación Estructura-Actividad
12.
J Bone Miner Res ; 18(11): 2033-42, 2003 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-14606517

RESUMEN

UNLABELLED: CP-533,536, a newly discovered, non-prostanoid EP2 receptor-selective PGE2 agonist, stimulates local bone formation and enhances fracture healing in rat models. INTRODUCTION: There is a significant medical need for agents that can stimulate local bone formation and enhance fracture healing. We tested the effects of CP-533,536, a newly discovered, non-prostanoid EP2 receptor-selective prostaglandin E2 (PGE2) agonist, in stimulating local bone formation and enhancing fracture healing in rat models. MATERIALS AND METHODS: In the first model, a single injection of CP-533,536 at doses of 0.3, 1, or 3 mg/kg to the proximal tibial metaphysis of 6-week-old male rats was given on day 1, and the local bone anabolic effect was determined on day 7. We then tested the effects of this compound in inducing bone formation on rat periosteum of the femur. A single dose of 0.3 mg of CP-533,536 incorporated in a poly-(D,L-lactide-co-glycolide) (PLGH) matrix was injected onto the periosteum of the femur in 3-week-old male rats, and local bone formation was determined on day 14. Finally, the ability of CP-533,536 in PLGH matrix in enhancing fracture healing was tested using the rat femoral fracture model. CP-533,536 in PLGH matrix at doses of 0.05, 0.5, or 5 mg was delivered to the local fracture site on the same day of fracture, and its efficacy was evaluated on day 21. RESULTS AND CONCLUSIONS: A single injection of CP-533,536 at doses of 0.3, 1, or 3 mg/kg to the proximal tibial metaphysis dose-dependently stimulated local lamellar bone formation on trabecular, endocortical, and periosteal surfaces, and thus increased bone mineral content and bone strength at the injected site. Similarly, a single injection of 0.3 mg of CP-533,536 incorporated in PLGH matrix onto the periosteum of the femur induced significantly local bone formation. In the rat femoral fracture model, CP-533,536 in PLGH matrix at doses of 0.05, 0.5, and 5 mg dose-dependently increased callus size, density, and strength compared with PLGH matrix alone. These results show that CP-533,536 stimulates new bone formation on trabecular, endocortical, and periosteal surfaces and enhances fracture healing. These data reveal that EP2 receptor-selective agonists provide therapeutic potential for local bone augmentation, bone repair, and bone healing in humans.


Asunto(s)
Huesos/efectos de los fármacos , Dinoprostona/agonistas , Fracturas del Fémur/tratamiento farmacológico , Curación de Fractura/efectos de los fármacos , Piridinas/farmacología , Piridinas/uso terapéutico , Receptores de Prostaglandina E/metabolismo , Animales , Huesos/fisiología , Modelos Animales de Enfermedad , Fluorescencia , Inyecciones , Masculino , Estructura Molecular , Piridinas/administración & dosificación , Ratas , Ratas Sprague-Dawley , Subtipo EP2 de Receptores de Prostaglandina E , Especificidad por Sustrato
13.
J Med Chem ; 54(6): 1948-52, 2011 Mar 24.
Artículo en Inglés | MEDLINE | ID: mdl-21361292

RESUMEN

The synthesis and properties of the bridged piperidine (oxaazabicyclo) compounds 8, 9, and 11 are described. A conformational analysis of these structures is compared with the representative GPR119 ligand 1. These results and the differences in agonist pharmacology are used to formulate a conformation-based hypothesis to understand activation of the GPR119 receptor. We also show for these structures that the agonist pharmacology in rat masks the important differences in human pharmacology.


Asunto(s)
Compuestos de Azabiciclo/química , Compuestos de Azabiciclo/farmacología , Pirimidinas/química , Pirimidinas/farmacología , Receptores Acoplados a Proteínas G/agonistas , Animales , Compuestos de Azabiciclo/síntesis química , Prueba de Tolerancia a la Glucosa , Humanos , Conformación Molecular , Pirimidinas/síntesis química , Ratas , Receptores Acoplados a Proteínas G/antagonistas & inhibidores , Especificidad de la Especie , Estereoisomerismo , Relación Estructura-Actividad
14.
J Med Chem ; 51(21): 7010-4, 2008 Nov 13.
Artículo en Inglés | MEDLINE | ID: mdl-18921992

RESUMEN

4-((1 R,2 R)-2-Hydroxycyclohexyl)-2(trifluoromethyl)benzonitrile [PF-0998425, (-)- 6a] is a novel, nonsteroidal androgen receptor antagonist for sebum control and treatment of androgenetic alopecia. It is potent, selective, and active in vivo. The compound is rapidly metabolized systemically, thereby reducing the risk of unwanted systemic side effects due to its primary pharmacology. (-)- 6a was tested negative in the 3T3 NRU assay, validating our rationale that reduction of conjugation might reduce potential phototoxicity.


Asunto(s)
Antagonistas de Receptores Androgénicos , Ciclohexanoles/síntesis química , Ciclohexanoles/farmacología , Nitrilos/síntesis química , Nitrilos/farmacología , Fármacos Fotosensibilizantes/síntesis química , Fármacos Fotosensibilizantes/farmacología , Piel , Cristalografía por Rayos X , Ciclohexanoles/química , Diseño de Fármacos , Ligandos , Modelos Moleculares , Estructura Molecular , Nitrilos/química , Fármacos Fotosensibilizantes/química , Receptores Androgénicos/química , Receptores Androgénicos/metabolismo , Piel/efectos de los fármacos , Piel/metabolismo , Esteroides/química , Relación Estructura-Actividad
15.
Bioorg Med Chem Lett ; 16(7): 1799-802, 2006 Apr 01.
Artículo en Inglés | MEDLINE | ID: mdl-16442794

RESUMEN

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 E
17.
Bioorg Med Chem Lett ; 12(22): 3279-82, 2002 Nov 18.
Artículo en Inglés | MEDLINE | ID: mdl-12392732

RESUMEN

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.


Asunto(s)
Piperidinas/farmacocinética , Pirazoles/farmacocinética , Administración Oral , Animales , Disponibilidad Biológica , Perros , Hormona del Crecimiento/efectos de los fármacos , Sustancias de Crecimiento/metabolismo , Semivida , Interacciones Hidrofóbicas e Hidrofílicas , Factor I del Crecimiento Similar a la Insulina/efectos de los fármacos , Masculino , Piperidinas/administración & dosificación , Piperidinas/síntesis química , Pirazoles/administración & dosificación , Pirazoles/síntesis química , Ratas , Ratas Wistar , Relación Estructura-Actividad
18.
Bioorg Med Chem ; 11(4): 581-90, 2003 Feb 20.
Artículo en Inglés | MEDLINE | ID: mdl-12538023

RESUMEN

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/farmacología
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