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1.
Nat Commun ; 14(1): 5938, 2023 09 23.
Article in English | MEDLINE | ID: mdl-37741852

ABSTRACT

GPR61 is an orphan GPCR related to biogenic amine receptors. Its association with phenotypes relating to appetite makes it of interest as a druggable target to treat disorders of metabolism and body weight, such as obesity and cachexia. To date, the lack of structural information or a known biological ligand or tool compound has hindered comprehensive efforts to study GPR61 structure and function. Here, we report a structural characterization of GPR61, in both its active-like complex with heterotrimeric G protein and in its inactive state. Moreover, we report the discovery of a potent and selective small-molecule inverse agonist against GPR61 and structural elucidation of its allosteric binding site and mode of action. These findings offer mechanistic insights into an orphan GPCR while providing both a structural framework and tool compound to support further studies of GPR61 function and modulation.


Subject(s)
Drug Inverse Agonism , GTP-Binding Proteins , Receptors, G-Protein-Coupled , Allosteric Site , Appetite , Binding Sites , GTP-Binding Proteins/metabolism , Humans , Receptors, G-Protein-Coupled/agonists
2.
Bioorg Med Chem Lett ; 92: 129394, 2023 Aug 15.
Article in English | MEDLINE | ID: mdl-37379958

ABSTRACT

Our previous work on the optimization of a new class of small molecule PCSK9 mRNA translation inhibitors focused on empirical optimization of the amide tail region of the lead PF-06446846 (1). This work resulted in compound 3 that showed an improved safety profile. We hypothesized that this improvement was related to diminished binding of 3 to non-translating ribosomes and an apparent improvement in transcript selectivity. Herein, we describe our efforts to further optimize this series of inhibitors through modulation of the heterocyclic head group and the amine fragment. Some of the effort was guided by an emerging cryo electron microscopy structure of the binding mode of 1 in the ribosome. These efforts led to the identification of 15 that was deemed suitable for evaluation in a humanized PCSK9 mouse model and a rat toxicology study. Compound 15 demonstrated a dose dependent reduction of plasma PCSK9 levels. The rat toxicological profile was not improved over that of 1, which precluded 15 from further consideration as a clinical candidate.

3.
J Med Chem ; 65(22): 15000-15013, 2022 11 24.
Article in English | MEDLINE | ID: mdl-36322383

ABSTRACT

Discovery efforts leading to the identification of ervogastat (PF-06865571), a systemically acting diacylglycerol acyltransferase (DGAT2) inhibitor that has advanced into clinical trials for the treatment of non-alcoholic steatohepatitis (NASH) with liver fibrosis, are described herein. Ervogastat is a first-in-class DGAT2 inhibitor that addressed potential development risks of the prototype liver-targeted DGAT2 inhibitor PF-06427878. Key design elements that culminated in the discovery of ervogastat are (1) replacement of the metabolically labile motif with a 3,5-disubstituted pyridine system, which addressed potential safety risks arising from a cytochrome P450-mediated O-dearylation of PF-06427878 to a reactive quinone metabolite precursor, and (2) modifications of the amide group to a 3-THF group, guided by metabolite identification studies coupled with property-based drug design.


Subject(s)
Diacylglycerol O-Acyltransferase , Non-alcoholic Fatty Liver Disease , Humans , Drug Design , Liver Cirrhosis , Non-alcoholic Fatty Liver Disease/drug therapy
4.
Angew Chem Int Ed Engl ; 61(30): e202205454, 2022 Jul 25.
Article in English | MEDLINE | ID: mdl-35587213

ABSTRACT

In this paper is described an easily synthesized chiral diazaborolidine that is inexpensive, stable, and provides excellent stereoselection across a number of reaction classes. These versatile compounds possess utility in four different classes of cycloaddition reactions, offering good yield and stereoselectivity. X-ray structure analysis provides insight about the origin of stereocontrol.

5.
J Am Chem Soc ; 144(18): 8296-8305, 2022 05 11.
Article in English | MEDLINE | ID: mdl-35486956

ABSTRACT

Aryl halides are a fundamental motif in synthetic chemistry, playing a critical role in metal-mediated cross-coupling reactions and serving as important scaffolds in drug discovery. Although thermal decarboxylative functionalization of aryl carboxylic acids has been extensively explored, the scope of existing halodecarboxylation methods remains limited, and there currently exists no unified strategy that provides access to any type of aryl halide from an aryl carboxylic acid precursor. Herein, we report a general catalytic method for direct decarboxylative halogenation of (hetero)aryl carboxylic acids via ligand-to-metal charge transfer. This strategy accommodates an exceptionally broad scope of substrates. We leverage an aryl radical intermediate toward divergent functionalization pathways: (1) atom transfer to access bromo- or iodo(hetero)arenes or (2) radical capture by copper and subsequent reductive elimination to generate chloro- or fluoro(hetero)arenes. The proposed ligand-to-metal charge transfer mechanism is supported through an array of spectroscopic studies.


Subject(s)
Carboxylic Acids , Halogenation , Carboxylic Acids/chemistry , Catalysis , Copper/chemistry , Ligands
6.
J Am Chem Soc ; 144(14): 6163-6172, 2022 04 13.
Article in English | MEDLINE | ID: mdl-35377627

ABSTRACT

We report a copper-catalyzed strategy for arylboronic ester synthesis that exploits photoinduced ligand-to-metal charge transfer (LMCT) to convert (hetero)aryl acids into aryl radicals amenable to ambient-temperature borylation. This near-UV process occurs under mild conditions, requires no prefunctionalization of the native acid, and operates broadly across diverse aryl, heteroaryl, and pharmaceutical substrates. We also report a one-pot procedure for decarboxylative cross-coupling that merges catalytic LMCT borylation and palladium-catalyzed Suzuki-Miyaura arylation, vinylation, or alkylation with organobromides to access a range of value-added products. The utility of these protocols is highlighted through the development of a heteroselective double-decarboxylative C(sp2)-C(sp2) coupling sequence, pairing copper-catalyzed LMCT borylation and halogenation processes of two distinct acids (including pharmaceutical substrates) with subsequent Suzuki-Miyaura cross-coupling.


Subject(s)
Copper , Palladium , Catalysis , Pharmaceutical Preparations
7.
Org Lett ; 23(8): 2863-2867, 2021 04 16.
Article in English | MEDLINE | ID: mdl-33792325

ABSTRACT

The Pt-catalyzed diboration of cyclic alkenes is extended to unsaturated heterocycles and bicyclic compounds and can be accomplished in a diastereoselective fashion. The optimal procedures, substrate scope, and diastereoselectivity were investigated, and examples employing both homogeneous and heterogeneous catalysis were examined. Lastly, application to the construction of the nucleoside analog (±)-aristeromycin was conducted.

8.
Org Lett ; 23(9): 3379-3383, 2021 05 07.
Article in English | MEDLINE | ID: mdl-33852313

ABSTRACT

Intramolecular amination of organoboronates occurs with a 1,2-metalate shift of an aminoboron "ate" complex to form azetidines, pyrrolidines, and piperidines. Bis(boronates) undergo site-selective amination to form boronate-containing azacycles. Enantiomerically enriched azacycles are formed with high stereospecificity.

9.
Angew Chem Int Ed Engl ; 56(51): 16218-16222, 2017 12 18.
Article in English | MEDLINE | ID: mdl-29073340

ABSTRACT

Targeting of the human ribosome is an unprecedented therapeutic modality with a genome-wide selectivity challenge. A liver-targeted drug candidate is described that inhibits ribosomal synthesis of PCSK9, a lipid regulator considered undruggable by small molecules. Key to the concept was the identification of pharmacologically active zwitterions designed to be retained in the liver. Oral delivery of the poorly permeable zwitterions was achieved by prodrugs susceptible to cleavage by carboxylesterase 1. The synthesis of select tetrazole prodrugs was crucial. A cell-free in vitro translation assay containing human cell lysate and purified target mRNA fused to a reporter was used to identify active zwitterions. In vivo PCSK9 lowering by oral dosing of the candidate prodrug and quantification of the drug fraction delivered to the liver utilizing an oral positron emission tomography 18 F-isotopologue validated our liver-targeting approach.


Subject(s)
Liver/drug effects , PCSK9 Inhibitors , Proprotein Convertase 9/biosynthesis , Small Molecule Libraries/pharmacology , Dose-Response Relationship, Drug , Hepatocytes/drug effects , Hepatocytes/metabolism , Humans , Liver/enzymology , Liver/metabolism , Molecular Structure , Proprotein Convertase 9/metabolism , Small Molecule Libraries/chemistry , Structure-Activity Relationship
10.
J Am Chem Soc ; 138(14): 4818-23, 2016 Apr 13.
Article in English | MEDLINE | ID: mdl-27003237

ABSTRACT

We report a modular three-component dynamic kinetic resolution (DKR) that affords enantiomerically enriched hemiaminal esters derived from azoles and aldehydes. The novel and scalable reaction can be used to synthesize valuable substituted azoles in a regioselective manner by capping (e.g., acylation) of the equilibrating azole-aldehyde adduct. With the use of a prolinol-derived DMAP catalyst as the chiral Lewis base, the products can be obtained in high chemical yield and with high enantiomeric excess. The DKR was performed on a multikilogram scale to produce a tetrazole prodrug fragment for a leading clinical candidate that posed formidable synthesis challenges.


Subject(s)
Azoles/chemical synthesis , Esters/chemical synthesis , Lewis Bases/chemistry , Aldehydes/chemistry , Alkanesulfonates/chemical synthesis , Alkanesulfonates/chemistry , Azoles/chemistry , Catalysis , Esters/chemistry , Kinetics , Stereoisomerism , Tetrazoles
11.
Org Lett ; 18(3): 508-11, 2016 Feb 05.
Article in English | MEDLINE | ID: mdl-26771228

ABSTRACT

The first described reaction between N-tosylhydrazone and SO2 is reported to provide alkyl sulfonamides in the presence of various amines. In this procedurally simple method, hydrazones of both unsaturated aldehydes and ketones proceed in moderate to excellent yields. Primary and secondary aliphatic amines are accommodated in this reaction, which provides a novel route to sulfonamides.


Subject(s)
Hydrazones/chemistry , Sulfonamides/chemical synthesis , Aldehydes/chemistry , Amines/chemistry , Catalysis , Ketones/chemistry , Molecular Structure , Sulfonamides/chemistry , Sulfur Dioxide/chemistry
12.
Nat Prod Rep ; 31(4): 504-13, 2014 Apr.
Article in English | MEDLINE | ID: mdl-24514754

ABSTRACT

Despite the longstanding importance of polyketide natural products in human medicine, nearly all commercial polyketide-based drugs are prepared through fermentation or semi-synthesis. The paucity of manufacturing routes involving de novo chemical synthesis reflects the inability of current methods to concisely address the preparation of these complex structures. Direct alcohol C-H bond functionalization via"C-C bond forming transfer hydrogenation" provides a powerful, new means of constructing type I polyketides that bypasses stoichiometric use of chiral auxiliaries, premetallated C-nucleophiles, and discrete alcohol-to-aldehyde redox reactions. Using this emergent technology, total syntheses of 6-deoxyerythronolide B, bryostatin 7, trienomycins A and F, cyanolide A, roxaticin, and formal syntheses of rifamycin S and scytophycin C, were accomplished. These syntheses represent the most concise routes reported to any member of the respective natural product families.


Subject(s)
Biological Products/chemical synthesis , Polyketides/chemical synthesis , Biological Products/chemistry , Bridged Bicyclo Compounds, Heterocyclic/chemical synthesis , Bridged Bicyclo Compounds, Heterocyclic/chemistry , Bryostatins/chemical synthesis , Bryostatins/chemistry , Catalysis , Erythromycin/analogs & derivatives , Erythromycin/chemical synthesis , Erythromycin/chemistry , Humans , Hydrogenation , Macrolides/chemical synthesis , Macrolides/chemistry , Molecular Structure , Polyketides/chemistry , Rifamycins/chemical synthesis , Rifamycins/chemistry , Stereoisomerism
13.
Chem Commun (Camb) ; 49(54): 6096-8, 2013 Jul 11.
Article in English | MEDLINE | ID: mdl-23722271

ABSTRACT

The ruthenium catalyst derived from Ru3(CO)12 and triphos [Ph2P(CH2CH2PPh2)2] promotes the direct C-C coupling of isoprene with aryl substituted hydantoins 1a­1f at the diene C4-position to furnish products of n-prenylation 2a­2f. A mechanism involving hydantoin dehydrogenation followed by diene-imine oxidative coupling to furnish a transient aza-ruthencyclopentene is proposed.


Subject(s)
Butadienes/chemistry , Hemiterpenes/chemistry , Hydantoins/chemistry , Pentanes/chemistry , Ruthenium/chemistry , Alkylation , Catalysis , Coordination Complexes/chemistry , Hydrogenation , Prenylation
15.
Org Lett ; 14(24): 6302-5, 2012 Dec 21.
Article in English | MEDLINE | ID: mdl-23231774

ABSTRACT

The cyclometalated π-allyliridium 3,4-dinitro-C,O-benzoate complex modified by (R)- or (S)-Cl,MeO-BIPHEP promotes the transfer hydrogenative coupling of allyl acetate to ß-stereogenic alcohols with good to excellent levels of catalyst-directed diastereoselectivity to furnish homoallylic alcohols. Remote electronic effects of the C,O-benzoate of the catalyst play a critical role in suppressing epimerization of the transient α-stereogenic aldehyde.


Subject(s)
Alcohols/chemistry , Aldehydes/chemistry , Iridium/chemistry , Alcohols/chemical synthesis , Catalysis , Molecular Structure , Stereoisomerism
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