Optimization of triazole-based TGR5 agonists towards orally available agents

Futatsugi, Kentaro; Bahnck, Kevin B.; Brenner, Martin; Buxton, Joanne M.; Chin, Janice E.; Coffey, Steven B.; Dubins, Jeffrey S.; Flynn, Declan; Gautreau, Denise; Guzmán-Pérez, Angel; Hadcock, John R.; Hepworth, David; Herr, Michael; Hinchey, Terri; Janssen, Ann M.; Jennings, Sandra; Jiao, Wenhua; Lavergne, Sophie Y.; Li, Bryan; Li, Mei; Munchhof, Michael J.; Orr, Suvi T. M.; Piotrowski, David W.; Roush, Nicole; Sammons, M. F.; Stevens, Benjamin D.; Storer, Gregory; Wang, Jian; Warmus, Joseph S.; Wei, Liuqing; Wolford, Angela

doi:10.1039/c2md20174g

Cited by 29 publications

(25 citation statements)

References 17 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Of significant note, treatment-dependent changes in heart rate and blood pressure were noted for 16 as well as for another compound from a distinct and highly dissimilar chemotype, 25 with no treatment-related changes to electrocardiogram waveform parameters. These data infer that a mechanismbased toxicity associated with systemic exposure of this compound is likely involved.…”

mentioning

confidence: 92%

“…Similar results were noted for a compound from a distinct and highly dissimilar chemotype. 25 Having established a correlation between our uninduced TGR5 assay and pharmacology in native systems, we then turned our attention toward identifying a tool compound for use in vivo that may be able to achieve levels of exposure consistent with these findings. To better understand the clearance profiles of compounds 14 and 16, in vitro metabolite identification studies using HLM in the presence and absence of reduced nicotinamide adenine dinucleotide phosphate (NADPH) cofactors were undertaken ( Figure S2 in the Supporting Information).…”

mentioning

confidence: 99%

See 1 more Smart Citation

Identification of Tetrahydropyrido[4,3-d]pyrimidine Amides as a New Class of Orally Bioavailable TGR5 Agonists

Piotrowski

Futatsugi

Warmus

et al. 2012

ACS Med. Chem. Lett.

Self Cite

View full text Add to dashboard Cite

Takeda G-protein-coupled receptor 5 (TGR5) represents an exciting biological target for the potential treatment of diabetes and metabolic syndrome. A new class of high-throughput screening (HTS)-derived tetrahydropyrido- [4,3-d]pyrimidine amide TGR5 agonists is disclosed. We describe our effort to identify an orally available agonist suitable for assessment of systemic TGR5 agonism. This effort resulted in identification of 16, which had acceptable potency and pharmacokinetic properties to allow for in vivo assessment in dog. A key aspect of this work was the calibration of human and dog in vitro assay systems that could be linked with data from a human ex vivo peripheral blood monocyte assay that expresses receptor at endogenous levels. Potency from the human in vitro assay was also found to correlate with data from an ex vivo human whole blood assay. This calibration exercise provided confidence that 16 could be used to drive plasma exposures sufficient to test the effects of systemic activation of TGR5. KEYWORDS: GPCR, TGR5, agonist, diabetes, GLP-1 T GR5 (Takeda G-protein-coupled receptor 5) is a class A G-protein-coupled receptor (GPCR) expressed in liver, skeletal muscle, intestine, brown adipose tissues, and monocytes. 1−4 Activation of the TGR5 receptor upon ligand binding results in Gα s -coupled activation of adenylate cyclase. The subsequent downstream signaling cascade is believed to drive multiple effects that are cell type-dependent including (1) enhanced glucagon-like peptide-1 (GLP-1) release from intestinal cells potentially offering improved glycemic control through potentiation of glucose-dependent insulin secretion; 5 (2) nuclear effects, such as endothelial nitric oxide synthase activation and increased nitric oxide production in liver cells; 6 and (3) reduction of macrophage inflammation and lipid loading leading to inhibition of atherosclerosis. 7,8 Activation of TGR5 can also induce type 2 iodothyronine deiodinase in brown adipose tissue. In mice, this leads to increased energy expenditure, but the picture is less clear for humans. 9,10 For these reasons, TGR5 agonists may be useful agents to not only treat diabetes with concurrent management of glucose levels and body weight but also potentially address other aspects of metabolic syndrome.Bile acids are the purported endogenous agonists for TGR5. Of the several bile acids that act as ligands, taurine-conjugated lithocholic acid, lithocholic acid, deoxycholic acid, chenodeoxycholic acid, and cholic acid have all been shown to dose dependently induce accumulation of cyclic adenosine 5′-monophosphate (cAMP) in TGR5-transfected Chinese hamster ovary (CHO) cells. 11 Significant effort has been devoted to synthetic bile acids, such as INT-777 (1). 12,13 In addition, several other nonbile acid agonists have been reported in the literature (2−4), 14−16 which offer the potential for higher selectivity over other bile acid-mediated pathways (Figure 1). Previous work with 1 demonstrated in vivo modulation of

show abstract

mentioning

confidence: 92%

mentioning

confidence: 99%

Identification of Tetrahydropyrido[4,3-d]pyrimidine Amides as a New Class of Orally Bioavailable TGR5 Agonists

Piotrowski

Futatsugi

Warmus

et al. 2012

ACS Med. Chem. Lett.

Self Cite

View full text Add to dashboard Cite

show abstract

“…Avoiding highly lipophilic compounds is a design principle used to improve clearance [50]. The analysis of matching pairs conducted by Stepan et al [11] confirmed that changes in metabolic stability largely come from changes in lipophilicity ( Figure 3).…”

Section: Lipophilicity and Clearancementioning

confidence: 90%

“…It is commonly measured by its distribution behavior in a biphasic system, either liquid-liquid by the following simplified equation in which N is the number of non-hydrogen atoms: LE = 1.37(-log IC 50 )/N . Project progress may be tracked using both LE and LipE; LipE is expected to reach values of 6 or 7 for a potential drug candidate to be chosen for further development [18][19][20].…”

Section: Lipophilicitymentioning

confidence: 99%

See 1 more Smart Citation

Leveraging chromatography based physicochemical properties for efficient drug design

Goetz

Shalaeva²

2018

ADMET DMPK

View full text Add to dashboard Cite

<p class="ADMETabstracttext">Applications of chromatography derived lipophilicity, polarity, and 3D concepts such as conformational states, exposed polarity and intramolecular hydrogen bonds (IMHB), are discussed along with recently developed methods for incorporating these concepts into drug design strategies. In addition, the drug design process is described with examples and practices used at Pfizer, as well as experimental and computed parameters used for parallel optimization of properties leading to drug candidate nominations.</p>

show abstract

Intramolecular Copper(I)‐Catalyzed Interrupted Click–Acylation Domino Reaction

Larin

Lautens

2019

Angewandte Chemie

View full text Add to dashboard Cite

Acyl substituted triazoles are valuable scaffolds, but the direct synthesis of these moieties from terminal alkynes by copper catalysis remains unexplored. We report a robust, general, and efficient method using a simple CuI/2,2′‐bipyridine catalytic system. This transformation involves a copper catalyzed azide‐alkyne cycloaddition (CuAAC) followed by an intramolecular acylation onto a carbamoyl chloride. The reaction proceeds under mild conditions, tolerates several functional groups, and is readily scalable. This method represents a novel strategy towards the synthesis of complex heterocycles by a CuAAC/acylation domino process.

show abstract

Optimization of triazole-based TGR5 agonists towards orally available agents

Abstract: With the challenge of striking the balance of TGR5 potency and clearance, the screening strategy as well as medicinal chemistry strategy are discussed in this article.

Cited by 29 publications

References 17 publications

Identification of Tetrahydropyrido[4,3-d]pyrimidine Amides as a New Class of Orally Bioavailable TGR5 Agonists

Identification of Tetrahydropyrido[4,3-d]pyrimidine Amides as a New Class of Orally Bioavailable TGR5 Agonists

Leveraging chromatography based physicochemical properties for efficient drug design

Intramolecular Copper(I)‐Catalyzed Interrupted Click–Acylation Domino Reaction

Contact Info

Product

Resources

About