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

ABSTRACT

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.


Subject(s)
Asialoglycoprotein Receptor/metabolism , Bridged Bicyclo Compounds/chemistry , Hepatocytes/metabolism , Ketones/chemistry , Liver/metabolism , Polymers/chemistry , Bridged Bicyclo Compounds/metabolism , Crystallography, X-Ray , Drug Carriers/chemistry , Humans , Ketones/metabolism , Liver/cytology , Models, Molecular , Molecular Structure , Polymers/metabolism
2.
Bioorg Med Chem Lett ; 23(1): 194-7, 2013 Jan 01.
Article in English | MEDLINE | ID: mdl-23177788

ABSTRACT

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).


Subject(s)
Pyrazoles/chemistry , Receptors, G-Protein-Coupled/agonists , Carbamates/chemistry , Humans , Piperidines/chemistry , Protein Binding , Pyrazoles/chemical synthesis , Pyrazoles/metabolism , Receptors, G-Protein-Coupled/metabolism , Structure-Activity Relationship
3.
Angew Chem Int Ed Engl ; 52(40): 10607-10, 2013 Sep 27.
Article in English | MEDLINE | ID: mdl-23956102

ABSTRACT

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.


Subject(s)
Lactams/chemistry , Organometallic Compounds/chemistry , Catalysis , Kinetics , Models, Molecular , Molecular Structure , Stereoisomerism
4.
J Am Chem Soc ; 134(4): 1978-81, 2012 Feb 01.
Article in English | MEDLINE | ID: mdl-22280495

ABSTRACT

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.


Subject(s)
Acetylgalactosamine/chemistry , Asialoglycoprotein Receptor/chemistry , Acetylgalactosamine/analogs & derivatives , Humans , Ligands , Molecular Structure , Stereoisomerism
5.
J Org Chem ; 77(22): 10050-7, 2012 Nov 16.
Article in English | MEDLINE | ID: mdl-23127254

ABSTRACT

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.


Subject(s)
Acetyl-CoA Carboxylase/antagonists & inhibitors , Acetyl-CoA Carboxylase/chemistry , Lactams/chemistry , Lactams/chemical synthesis , Piperidines/chemistry , Piperidines/chemical synthesis , Pyrazoles/chemistry , Pyridones/chemistry , Pyridones/chemical synthesis , Alkylation , Cyclization , Molecular Structure , Stereoisomerism
6.
Chem Res Toxicol ; 24(2): 269-78, 2011 Feb 18.
Article in English | MEDLINE | ID: mdl-21288051

ABSTRACT

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.


Subject(s)
Glutathione/metabolism , Microsomes, Liver/drug effects , Microsomes, Liver/metabolism , Pyrimidines/metabolism , Receptors, G-Protein-Coupled/agonists , Animals , Diabetes Mellitus, Type 2/drug therapy , Glutathione/chemistry , Horses , Humans , Magnetic Resonance Spectroscopy , Mass Spectrometry , Molecular Structure , Pyrimidines/chemistry
7.
Bioorg Med Chem Lett ; 20(5): 1569-72, 2010 Mar 01.
Article in English | MEDLINE | ID: mdl-20149653

ABSTRACT

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.


Subject(s)
Glycosides/chemistry , Hypoglycemic Agents/chemistry , Sodium-Glucose Transporter 2 Inhibitors , Spiro Compounds/chemistry , Animals , Cyclization , Glycosides/chemical synthesis , Glycosides/pharmacokinetics , Humans , Hypoglycemic Agents/chemical synthesis , Hypoglycemic Agents/pharmacokinetics , Male , Microsomes, Liver/metabolism , Rats , Rats, Sprague-Dawley , Sodium-Glucose Transporter 2/metabolism
8.
Acta Crystallogr Sect E Struct Rep Online ; 66(Pt 6): o1386, 2010 May 19.
Article in English | MEDLINE | ID: mdl-21579467

ABSTRACT

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.
Article in English | MEDLINE | ID: mdl-33062185

ABSTRACT

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.
Article in English | MEDLINE | ID: mdl-32809824

ABSTRACT

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.


Subject(s)
Acetyl-CoA Carboxylase/antagonists & inhibitors , Drug Delivery Systems , Enzyme Inhibitors/pharmacology , Liver/drug effects , Acetyl-CoA Carboxylase/metabolism , Animals , Enzyme Inhibitors/therapeutic use , Humans , Lipogenesis , Non-alcoholic Fatty Liver Disease/drug therapy , Substrate Specificity
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