Evaluation and Synthesis of Polar Aryl- and Heteroaryl Spiroazetidine-Piperidine Acetamides as Ghrelin Inverse Agonists

Orr, Suvi T. M.; Beveridge, Ramsay E.; Bhattacharya, Samit; Cameron, Kimberly O.; Coffey, Steven B.; Fernando, Dilinie P.; Hepworth, David; Jackson, Margaret; Khot, Vishal; Kosa, Rachel E.; Lapham, Kimberly; Loria, Paula M.; McClure, Kim F.; Patel, Jigna D.; Rose, Colin R.; Sáenz, James; Stock, Ingrid A.; Storer, Gregory; Volkenburg, Maria von; Vrieze, Derek; Wang, Guoqiang; Xiao, Jun; Zhang, Yingxin

doi:10.1021/ml500414n

Cited by 15 publications

(6 citation statements)

References 37 publications

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Section: Resultsmentioning

confidence: 97%

“…Despite the attractive features of the synthesis, initial attempts to convert 27 to hydrazide 32 proved troublesome, as has been previously reported in the literature for hydrolysis of such tert-butyl cyanoacetate adducts. 64 Hydrolysis of 27 with aqueous acid resulted in the formation of side products 17 and 30 (Figure 7B). Methylpyridine 17 resulted from overdecarboxylation of the unstable acid intermediate 29 under highly acidic conditions, whereas tert-butyl amide 30 was generated via a Ritter reaction between intermediate nitrile 28 and the isobutylene liberated from the acid-mediated decarboxylation of tert-butyl ester 27.…”

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confidence: 99%

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Development of Two Synthetic Approaches to an APJ Receptor Agonist Containing a Tetra-ortho-Substituted Biaryl Pyridone

Goldfogel

Jamison

Savage

et al. 2021

Org. Process Res. Dev.

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The development and implementation of two process syntheses to provide BMS-986224, an agonist of the APJ receptor, are reported. The first-generation synthesis of BMS-986224 relied on a key enamine cyclization to construct the pyridone core; however, the overall efficiency of this route was limited by the linear synthesis of the hindered biaryl pyridone. This lack of convergence is solved in a second-generation route that minimizes low-temperature lithiation chemistry, replaces costly Pd coupling with scalable nucleophilic arylation, and reduces step count. The improved synthesis was enabled by a new Negishi coupling method that addresses limitations of the Suzuki−Miyaura literature for tetra-ortho-substituted biaryl pyridones.

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Section: Resultsmentioning

confidence: 97%

mentioning

confidence: 99%

Development of Two Synthetic Approaches to an APJ Receptor Agonist Containing a Tetra-ortho-Substituted Biaryl Pyridone

Goldfogel

Jamison

Savage

et al. 2021

Org. Process Res. Dev.

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show abstract

“…measurements and biological activities. [103][104][105][106][107][108][109][110][111][112][113][114] In some cases, the experimental logP N , pK a, and log P app IP were reported, but otherwise they were determined using ChemAxon. The LipE was then simulated using Equation 1 and Equation 2 and compared to their experimental values.…”

Section: Experimental Data Of Lipophilicity-based Applications and Me...mentioning

confidence: 99%

Critical Assessment of pH‐Dependent Lipophilicity Profiles of Small Molecules: Which One Should We Use and In Which Cases?

Bertsch,

Suñer,

Pinheiro

et al. 2023

ChemPhysChem

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Lipophilicity is a physicochemical property with wide relevance in drug design, computational biology, and food, environmental and medicinal chemistry. Lipophilicity is commonly expressed as the partition coefficient for neutral molecules, whereas for molecules with ionizable groups, the distribution coefficient (D) at a given pH is used. The logDpH is usually predicted using a pH correction, while often ignoring the apparent ionic partition [[EQUATION]]. In this work, we studied the impact of [[EQUATION]] on the prediction of both the experimental lipophilicity of small molecules and experimental lipophilicity‐based applications and metrics such as lipophilic efficiency (LipE), distribution of spiked drugs in milk products, and pH‐dependent partition of water contaminants in synthetic passive samples such as silicones. Our findings show that better predictions are obtained by considering the apparent ionic partition. In this context, we developed machine learning algorithms to determine the cases that [[EQUATION]] should be considered. The results indicate that small, rigid, and unsaturated molecules with logPN close to zero, which present a significant proportion of ionic species in the aqueous phase, were better modeled using the apparent ionic partition [[EQUATION]]). Finally, our findings can serve as guidance to the scientific community working in early‐stage drug design, food, and environmental chemistry

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“…82 Starting from lead 43, another series of spiro-azetidinepiperidine derivatives was also developed to improve potency, PK, and the safety profile by emphasizing increased polarity of the compounds. 83 Compound 45 (K i = 9.2 nM) (Figure 11C), endowed with an optimal combination of potency, polarity, and in vivo PK properties, was obtained. However, owing to pH-dependent chemical instability of the ortho-carboxamide function, its further development was discontinued.…”

Section: Medicinal Chemistry Of Ghs-r1a Ligandsmentioning

confidence: 99%

Advances in the Development of Nonpeptide Small Molecules Targeting Ghrelin Receptor

et al. 2022

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Ghrelin is an octanoylated peptide acting by the activation of the growth hormone secretagogue receptor, namely, GHS-R1a. The involvement of ghrelin in several physiological processes, including stimulation of food intake, gastric emptying, body energy balance, glucose homeostasis, reduction of insulin secretion, and lipogenesis validates the considerable interest in GHS-R1a as a promising target for the treatment of numerous disorders. Over the years, several GHS-R1a ligands have been identified and some of them have been extensively studied in clinical trials. The recently resolved structures of GHS-R1a bound to ghrelin or potent ligands have provided useful information for the design of new GHS-R1a drugs. This perspective is focused on the development of recent nonpeptide small molecules acting as GHS-R1a agonists, antagonists, and inverse agonists, bearing classical or new molecular scaffolds, as well as on radiolabeled GHS-R1a ligands developed for imaging. Moreover, the pharmacological effects of the most studied ligands have been discussed.

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Evaluation and Synthesis of Polar Aryl- and Heteroaryl Spiroazetidine-Piperidine Acetamides as Ghrelin Inverse Agonists

Cited by 15 publications

References 37 publications

Development of Two Synthetic Approaches to an APJ Receptor Agonist Containing a Tetra-ortho-Substituted Biaryl Pyridone

Development of Two Synthetic Approaches to an APJ Receptor Agonist Containing a Tetra-ortho-Substituted Biaryl Pyridone

Critical Assessment of pH‐Dependent Lipophilicity Profiles of Small Molecules: Which One Should We Use and In Which Cases?

Advances in the Development of Nonpeptide Small Molecules Targeting Ghrelin Receptor

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