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1.
J Am Chem Soc ; 139(9): 3528-3536, 2017 03 08.
Artículo en Inglés | MEDLINE | ID: mdl-28230359

RESUMEN

A compact and stable bicyclic bridged ketal was developed as a ligand for the asialoglycoprotein receptor (ASGPR). This compound showed excellent ligand efficiency, and the molecular details of binding were revealed by the first X-ray crystal structures of ligand-bound ASGPR. This analogue was used to make potent di- and trivalent binders of ASGPR. Extensive characterization of the function of these compounds showed rapid ASGPR-dependent cellular uptake in vitro and high levels of liver/plasma selectivity in vivo. Assessment of the biodistribution in rodents of a prototypical Alexa647-labeled trivalent conjugate showed selective hepatocyte targeting with no detectable distribution in nonparenchymal cells. This molecule also exhibited increased ASGPR-directed hepatocellular uptake and prolonged retention compared to a similar GalNAc derived trimer conjugate. Selective release in the liver of a passively permeable small-molecule cargo was achieved by retro-Diels-Alder cleavage of an oxanorbornadiene linkage, presumably upon encountering intracellular thiol. Therefore, the multicomponent construct described here represents a highly efficient delivery vehicle to hepatocytes.


Asunto(s)
Receptor de Asialoglicoproteína/metabolismo , Compuestos Bicíclicos con Puentes/química , Hepatocitos/metabolismo , Cetonas/química , Hígado/metabolismo , Polímeros/química , Compuestos Bicíclicos con Puentes/metabolismo , Cristalografía por Rayos X , Portadores de Fármacos/química , Humanos , Cetonas/metabolismo , Hígado/citología , Modelos Moleculares , Estructura Molecular , Polímeros/metabolismo
2.
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
3.
Angew Chem Int Ed Engl ; 52(40): 10607-10, 2013 Sep 27.
Artículo en Inglés | MEDLINE | ID: mdl-23956102

RESUMEN

Two regioselective and complementary hydroarylation reactions of an unsymmetrical cyclic olefin have been developed. The products can be transformed in one step into constrained γ-amino acids. Regioselective arylation of Vince lactam is controlled by the choice of phosphine ligand enantiomer and the substituent on the amide nitrogen atom. The method was extended to a general regiodivergent parallel kinetic resolution of the racemic lactam.


Asunto(s)
Lactamas/química , Compuestos Organometálicos/química , Catálisis , Cinética , Modelos Moleculares , Estructura Molecular , Estereoisomerismo
4.
J Am Chem Soc ; 134(4): 1978-81, 2012 Feb 01.
Artículo en Inglés | MEDLINE | ID: mdl-22280495

RESUMEN

The asialoglycoprotein receptor (ASGPR) is a high-capacity galactose-binding receptor expressed on hepatocytes that binds its native substrates with low affinity. More potent ligands are of interest for hepatic delivery of therapeutic agents. We report several classes of galactosyl analogues with varied substitution at the anomeric, C2-, C5-, and C6-positions. Significant increases in binding affinity were noted for several trifluoromethylacetamide derivatives without covalent attachment to the protein. A variety of new ligands were obtained with affinity for ASGPR as good as or better than that of the parent N-acetylgalactosamine, showing that modification on either side of the key C3,C4-diol moiety is well tolerated, consistent with previous models of a shallow binding pocket. The galactosyl pyranose motif therefore offers many opportunities for the attachment of other functional units or payloads while retaining low-micromolar or better affinity for the ASGPR.


Asunto(s)
Acetilgalactosamina/química , Receptor de Asialoglicoproteína/química , Acetilgalactosamina/análogos & derivados , Humanos , Ligandos , Estructura Molecular , Estereoisomerismo
5.
J Org Chem ; 77(22): 10050-7, 2012 Nov 16.
Artículo en Inglés | MEDLINE | ID: mdl-23127254

RESUMEN

The synthesis of 4',6'-dihydrospiro[piperidine-4,5'-pyrazolo[3,4-c]pyridin]-7'(2'H)-one-based acetyl-CoA carboxylase inhibitors is reported. The hitherto unknown N-2 tert-butyl pyrazolospirolactam core was synthesized from ethyl 3-amino-1H-pyrazole-4-carboxylate in a streamlined 10-step synthesis requiring only one chromatography procedure. The described synthetic strategy provides pyrazolo-fused spirolactams from halogenated benzylic arenes and cyclic carboxylates. Key steps include a regioselective pyrazole alkylation providing the N-2 tert-butyl pyrazole and a Curtius rearrangement under both conventional and flow conditions to install the hindered amine via a stable and isolable isocyanate. Finally, a Parham-type cyclization was used to furnish the desired spirolactam. An analogous route provided efficient access to the related N-1 isopropyl lactam series. Elaboration of the lactam cores via amidation enabled synthesis of novel ACC inhibitors and the identification of potent analogues.


Asunto(s)
Acetil-CoA Carboxilasa/antagonistas & inhibidores , Acetil-CoA Carboxilasa/química , Lactamas/química , Lactamas/síntesis química , Piperidinas/química , Piperidinas/síntesis química , Pirazoles/química , Piridonas/química , Piridonas/síntesis química , Alquilación , Ciclización , Estructura Molecular , Estereoisomerismo
6.
Chem Res Toxicol ; 24(2): 269-78, 2011 Feb 18.
Artículo en Inglés | MEDLINE | ID: mdl-21288051

RESUMEN

Isopropyl 9-anti-[5-cyano-6-(2-methyl-pyridin-3-yloxy)-pyrimidin-4-yloxy]-3-oxa-7-aza-bicyclo[3.3.1]nonane-7-carboxylate (1) represents a prototypic compound from a lead chemical series of G protein-coupled receptor 119 agonists, intended for treatment of type 2 diabetes. When compound 1 was incubated with NADPH-supplemented human liver microsomes in the presence of glutathione, two thioether conjugates M4-1 and M5-1 were observed. Omission of NADPH from the microsomal incubations prevented the formation of M5-1 but not M4-1. The formation of M4-1 was also discerned in incubations of 1 and glutathione with human liver cytosol, partially purified glutathione transferase, and in phosphate buffer at pH 7.4. M4-1 was isolated, and its structure ascertained from LC-MS/MS and NMR analysis. The mass spectral and NMR data suggested that M4-1 was obtained from a nucleophilic displacement of the 6-(2-methylpyridin-3-yloxy) group in 1 by glutathione. In addition, mass spectral studies revealed that M5-1 was derived from an analogous displacement reaction on a monohydroxylated metabolite of 1; the regiochemistry of hydroxylation was established to be on the isopropyl group. Of great interest were the findings that replacement of the 5-cyano group in 1 with a 5-methyl group resulted in 2, which was practically inert toward reaction with glutathione. This observation suggests that the electron-withdrawing potential of the C5 cyano group serves to increase the electrophilicity of the C6 carbon (via stabilization of the transition state) and favors reaction with the nucleophilic thiol. The mechanistic insights gained from these studies should assist medicinal chemistry efforts toward the design of analogs that retain primary pharmacology but are latent toward reaction with biological nucleophiles, thus mitigating the potential for toxicological outcome due to adduction with glutathione or proteins.


Asunto(s)
Glutatión/metabolismo , Microsomas Hepáticos/efectos de los fármacos , Microsomas Hepáticos/metabolismo , Pirimidinas/metabolismo , Receptores Acoplados a Proteínas G/agonistas , Animales , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Glutatión/química , Caballos , Humanos , Espectroscopía de Resonancia Magnética , Espectrometría de Masas , Estructura Molecular , Pirimidinas/química
7.
Bioorg Med Chem Lett ; 20(5): 1569-72, 2010 Mar 01.
Artículo en Inglés | MEDLINE | ID: mdl-20149653

RESUMEN

Modifications to the sugar portion of C-aryl glycoside sodium glucose transporter 2 (SGLT2) inhibitors were explored, including systematic deletion and modification of each of the glycoside hydroxyl groups. Based on results showing activity to be quite tolerant of structural change at the C-5 position, a series of novel C-5 spiro analogues was prepared. Some of these analogues exhibit low nanomolar potency versus SGLT2 and promote urinary glucose excretion (UGE) in rats. However, due to sub-optimal pharmacokinetic parameters (in particular half-life), predicted human doses did not meet criteria for further advancement.


Asunto(s)
Glicósidos/química , Hipoglucemiantes/química , Inhibidores del Cotransportador de Sodio-Glucosa 2 , Compuestos de Espiro/química , Animales , Ciclización , Glicósidos/síntesis química , Glicósidos/farmacocinética , Humanos , Hipoglucemiantes/síntesis química , Hipoglucemiantes/farmacocinética , Masculino , Microsomas Hepáticos/metabolismo , Ratas , Ratas Sprague-Dawley , Transportador 2 de Sodio-Glucosa/metabolismo
8.
Acta Crystallogr Sect E Struct Rep Online ; 66(Pt 6): o1386, 2010 May 19.
Artículo en Inglés | MEDLINE | ID: mdl-21579467

RESUMEN

In the title compound, C(19)H(21)ClOS(2), the dithiane ring adopts a chair conformation. The dihedral angle between the benzene rings is 87.88 (4)°. In the crystal, inversion dimmers linked by pairs of C-H⋯O inter-actions occur.

9.
ACS Med Chem Lett ; 11(10): 2002-2009, 2020 Oct 08.
Artículo en Inglés | MEDLINE | ID: mdl-33062185

RESUMEN

The orexin system consists of two neuropeptides (orexin-A and orexin-B) that exert their mode of action on two receptors (orexin-1 and orexin-2). While the role of the orexin-2 receptor is established as an important modulator of sleep wake states, the role of the orexin-1 receptor is believed to play a role in addiction, panic, or anxiety. In this manuscript, we describe the optimization of a nonselective substituted azabicyclo[2.2.1]heptane dual orexin receptor antagonist (DORA) into orally bioavailable, brain penetrating, selective orexin-1 receptor (OX1R) antagonists. This resulted in the discovery of our first candidate for clinical development, JNJ-54717793.

10.
J Med Chem ; 63(19): 10879-10896, 2020 10 08.
Artículo en Inglés | MEDLINE | ID: mdl-32809824

RESUMEN

Preclinical and clinical data suggest that acetyl-CoA carboxylase (ACC) inhibitors have the potential to rebalance disordered lipid metabolism, leading to improvements in nonalcoholic steatohepatitis (NASH). Consistent with these observations, first-in-human clinical trials with our ACC inhibitor PF-05175157 led to robust reduction of de novo lipogenesis (DNL), albeit with concomitant reductions in platelet count, which were attributed to the inhibition of fatty acid synthesis within bone marrow. Herein, we describe the design, synthesis, and evaluation of carboxylic acid-based ACC inhibitors with organic anion transporting polypeptide (OATP) substrate properties, which facilitated selective distribution of the compounds at the therapeutic site of action (liver) relative to the periphery. These efforts led to the discovery of clinical candidate PF-05221304 (12), which selectively inhibits liver DNL in animals, while demonstrating considerable safety margins against platelet reduction in a nonhuman primate model.


Asunto(s)
Acetil-CoA Carboxilasa/antagonistas & inhibidores , Sistemas de Liberación de Medicamentos , Inhibidores Enzimáticos/farmacología , Hígado/efectos de los fármacos , Acetil-CoA Carboxilasa/metabolismo , Animales , Inhibidores Enzimáticos/uso terapéutico , Humanos , Lipogénesis , Enfermedad del Hígado Graso no Alcohólico/tratamiento farmacológico , Especificidad por Sustrato
11.
Front Pharmacol ; 8: 357, 2017.
Artículo en Inglés | MEDLINE | ID: mdl-28649201

RESUMEN

Orexin neurons originating in the perifornical and lateral hypothalamic area are highly reactive to anxiogenic stimuli and have strong projections to anxiety and panic-associated circuitry. Recent studies support a role for the orexin system and in particular the orexin 1 receptor (OX1R) in coordinating an integrative stress response. However, no selective OX1R antagonist has been systematically tested in two preclinical models of using panicogenic stimuli that induce panic attack in the majority of people with panic disorder, namely an acute hypercapnia-panic provocation model and a model involving chronic inhibition of GABA synthesis in the perifornical hypothalamic area followed by intravenous sodium lactate infusion. Here we report on a novel brain penetrant, selective and high affinity OX1R antagonist JNJ-54717793 (1S,2R,4R)-7-([(3-fluoro-2-pyrimidin-2-ylphenyl)carbonyl]-N-[5-(trifluoromethyl)pyrazin-2-yl]-7-azabicyclo[2.2.1]heptan-2-amine). JNJ-54717793 is a high affinity/potent OX1R antagonist and has an excellent selectivity profile including 50 fold versus the OX2R. Ex vivo receptor binding studies demonstrated that after oral administration JNJ-54717793 crossed the blood brain barrier and occupied OX1Rs in the rat brain. While JNJ-54717793 had minimal effect on spontaneous sleep in rats and in wild-type mice, its administration in OX2R knockout mice, selectively promoted rapid eye movement sleep, demonstrating target engagement and specific OX1R blockade. JNJ-54717793 attenuated CO2 and sodium lactate induced panic-like behaviors and cardiovascular responses without altering baseline locomotor or autonomic activity. These data confirm that selective OX1R antagonism may represent a novel approach of treating anxiety disorders, with no apparent sedative effects.

12.
J Med Chem ; 56(17): 7110-9, 2013 Sep 12.
Artículo en Inglés | MEDLINE | ID: mdl-23981033

RESUMEN

Acetyl-CoA carboxylase (ACC) catalyzes the rate-determining step in de novo lipogenesis and plays a crucial role in the regulation of fatty acid oxidation. Alterations in lipid metabolism are believed to contribute to insulin resistance; thus inhibition of ACC offers a promising option for intervention in type 2 diabetes mellitus. Herein we disclose a series of ACC inhibitors based on a spirocyclic pyrazololactam core. The lactam series has improved chemical and metabolic stability relative to our previously reported pyrazoloketone series, while retaining potent inhibition of ACC1 and ACC2. Optimization of the pyrazole and amide substituents led to quinoline amide 21, which was advanced to preclinical development.


Asunto(s)
Acetil-CoA Carboxilasa/antagonistas & inhibidores , Lactamas/farmacología , Animales , Área Bajo la Curva , Lactamas/química , Espectroscopía de Resonancia Magnética
13.
J Med Chem ; 54(8): 2952-60, 2011 Apr 28.
Artículo en Inglés | MEDLINE | ID: mdl-21449606

RESUMEN

Compound 4 (PF-04971729) belongs to a new class of potent and selective sodium-dependent glucose cotransporter 2 inhibitors incorporating a unique dioxa-bicyclo[3.2.1]octane (bridged ketal) ring system. In this paper we present the design, synthesis, preclinical evaluation, and human dose predictions related to 4. This compound demonstrated robust urinary glucose excretion in rats and an excellent preclinical safety profile. It is currently in phase 2 clinical trials and is being evaluated for the treatment of type 2 diabetes.


Asunto(s)
Compuestos Bicíclicos Heterocíclicos con Puentes/química , Compuestos Bicíclicos Heterocíclicos con Puentes/farmacología , Descubrimiento de Drogas , Inhibidores del Cotransportador de Sodio-Glucosa 2 , Animales , Área Bajo la Curva , Compuestos Bicíclicos Heterocíclicos con Puentes/farmacocinética , Cristalografía por Rayos X , Evaluación Preclínica de Medicamentos , Humanos , Espectroscopía de Resonancia Magnética , Espectrometría de Masas , Modelos Moleculares , Ratas
14.
Org Lett ; 12(13): 2940-3, 2010 Jul 02.
Artículo en Inglés | MEDLINE | ID: mdl-20527898

RESUMEN

A promising class of SGLT2 inhibitors bearing a unique dioxa-bicyclo[3.2.1]octane motif was recently disclosed. An improved stereoselective synthesis providing efficient access to one of the most potent and selective compounds from this class is reported. A one-pot deprotection/cyclization was used as the key step to form the dioxa-bicyclo[3.2.1]octane motif with full control of stereochemistry. Using an appropriately substituted aryl group, the route enables the synthesis of any given compound from the class.


Asunto(s)
Compuestos Bicíclicos Heterocíclicos con Puentes/síntesis química , Compuestos Bicíclicos Heterocíclicos con Puentes/química , Compuestos Bicíclicos Heterocíclicos con Puentes/farmacología , Conformación Molecular , Inhibidores del Cotransportador de Sodio-Glucosa 2 , Estereoisomerismo
15.
Org Biomol Chem ; 5(18): 2953-61, 2007 Sep 21.
Artículo en Inglés | MEDLINE | ID: mdl-17728861

RESUMEN

The synthesis of oligomeric glycocomimetics has been performed for targeting the Pseudomonas aeruginosa PA-IIL lectin, which is of therapeutical interest for anti-adhesive treatment. The disaccharide alpha-L-Fucp-(1-->4)-beta-D-GlcNAc, which is a high-affinity ligand of the lectin, has been coupled to dimeric and trimeric linkers with various lengths and geometries. A series of linear dimers displayed an efficient clustering effect and a very strong affinity, with a lower dissociation constant of 90 nM. The trimeric compound was less efficient in inhibition assays but displayed high affinity in solution. Titration microcalorimetry and molecular modeling allowed in-depth analysis and rationalization of the binding data. These glycoclusters could act by crosslinking the lectins present on the surface of bacteria and therefore interfere with host recognition or biofilm formation.


Asunto(s)
Disacáridos/química , Lectinas/química , Pseudomonas aeruginosa/química , Sitios de Unión , Calorimetría , Secuencia de Carbohidratos , Disacáridos/metabolismo , Lectinas/metabolismo , Espectroscopía de Resonancia Magnética , Modelos Moleculares , Datos de Secuencia Molecular , Pseudomonas aeruginosa/metabolismo , Espectrometría de Masa por Ionización de Electrospray
16.
ChemMedChem ; 2(9): 1328-38, 2007 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-17623286

RESUMEN

Pseudomonas aeruginosa is an opportunistic bacterium showing increasing resistance to antibiotics and consequently represents elevated threatening problems in hospital environments, particularly for cystic fibrosis patients. The use of glycomimetics as an anti-adhesive strategy against microorganisms may complement the use of antibiotics. PA-IIL lectin (LecB) from P. aeruginosa constitutes an appealing target for antibacterial agents, as it has been proposed to play a key role in binding to airway epithelia and/or to be involved in biofilm formation. The lectin has an unusually high affinity for L-fucose and related oligosaccharides. In the work presented herein, the disaccharide alphaFuc1-4GlcNAc is used as a scaffold toward the synthesis of a series of glycomimetic derivatives. Microcalorimetry and structural studies indicate that several of the derivatives are potent inhibitors of the lectin, with affinity in the same range as the best known natural ligand, Lewis a, and could represent interesting leads for the development of future antibacterial compounds.


Asunto(s)
Adhesinas Bacterianas/química , Disacáridos/química , Lectinas/química , Pseudomonas aeruginosa/química , Termodinámica , Cristalografía por Rayos X , Conformación Proteica
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