Synthesis and SAR of potent and orally bioavailable tert-butylpyrrolidine archetype derived melanocortin subtype-4 receptor modulators

Guo, Liangqin; Ye, Zhixiong; Ujjainwalla, Feroze; Sings, Heather L.; Sebhat, Iyassu K.; Huber, John D.; Weinberg, David H.; Tang, Rui; MacNeil, Tanya; Tamvakopoulos, Constantin; Peng, Qianping; MacIntyre, Euan; Ploeg, Lex H.T. Van der; Goulet, Mark T.; Wyvratt, Matthew J.; Nargund, Ravi P.

doi:10.1016/j.bmcl.2008.04.049

Cited by 16 publications

(13 citation statements)

References 15 publications

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“…reported a series of N- tert -butylpyrrolidine analogues ( 1 , Figure 3), maintaining the 4-chloro phenylpiperidine ring of MK0493 with an elongated ethyl group replacing the methyl next to the acetamide [147]. In efforts to improve MC4R binding and functional activity, they investigated aromatic substitutions to replace the 2,4-difluorophenyl group.…”

Section: Small Molecule Ligandsmentioning

confidence: 99%

“…In efforts to improve MC4R binding and functional activity, they investigated aromatic substitutions to replace the 2,4-difluorophenyl group. Both 4-chloro-2-fluorophenyl and 4-bromo-2-fluorophenyl substitutions increased affinity and agonist potency, indicating larger halogens in the 4-position may be beneficial [147]. In examining the affinity and functional effects of the trans diastereomers relative to the pyrrolidine ring ( 1 , stereocenters indicated by * and ** in Figure 3) of select compounds, they reported that the (*,** in Figure 3) S,R isomers acted as full agonists, while the R,S isomers maintained similar affinity but resulted in decreased cAMP production.…”

Section: Small Molecule Ligandsmentioning

confidence: 99%

“…In examining the affinity and functional effects of the trans diastereomers relative to the pyrrolidine ring ( 1 , stereocenters indicated by * and ** in Figure 3) of select compounds, they reported that the (*,** in Figure 3) S,R isomers acted as full agonists, while the R,S isomers maintained similar affinity but resulted in decreased cAMP production. This work resulted in several nanomolar ligands for the hMC4R [147]. …”

Section: Small Molecule Ligandsmentioning

confidence: 99%

“…Similar to the work by Guo et al . [147] investigating the two trans pyrrolidine diastereomers indicated the (*,** in Figure 3) S,R compound possessed high agonist activity while the R,S ligand possessed high affinity but was unable to stimulate cAMP production. Relatively small differences in potencies were observed when either a 2-fluoro or 4-methyl phenylpiperazine was used.…”

Section: Small Molecule Ligandsmentioning

confidence: 99%

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Bench-top to clinical therapies: A review of melanocortin ligands from 1954 to 2016

Ericson

Lensing

Fleming

et al. 2017

Biochimica et Biophysica Acta (BBA) - Molecular Basis of Diseas

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The discovery of the endogenous melanocortin agonists in the 1950s have resulted in sixty years of melanocortin ligand research. Early efforts involved truncations or select modifications of the naturally occurring agonists leading to the development of many potent and selective ligands. With the identification and cloning of the five known melanocortin receptors, many ligands were improved upon through bench-top in vitro assays. Optimization of select properties resulted in ligands adopted as clinical candidates. A summary of every melanocortin ligand is outside the scope of this review. Instead, this review will focus on the following topics: classic melanocortin ligands, selective ligands, small molecule (non-peptide) ligands, ligands with sex-specific effects, bivalent and multivalent ligands, and ligands advanced to clinical trials. Each topic area will be summarized with current references to update the melanocortin field on recent progress.

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Section: Small Molecule Ligandsmentioning

confidence: 99%

Section: Small Molecule Ligandsmentioning

confidence: 99%

Section: Small Molecule Ligandsmentioning

confidence: 99%

Section: Small Molecule Ligandsmentioning

confidence: 99%

See 2 more Smart Citations

Bench-top to clinical therapies: A review of melanocortin ligands from 1954 to 2016

Ericson

Lensing

Fleming

et al. 2017

Biochimica et Biophysica Acta (BBA) - Molecular Basis of Diseas

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“…6, bottom). agonist (13); sibutramine, a serotonin and norepinephrine reuptake inhibitor (27); and CL-316243, a selective ␤ 3 -adrenergic receptor agonist (4). Relatively high drug doses were used to ensure that the drug effects lasted for the duration of the assays.…”

Section: Brs-3 Agonists Increase Body Temperature Mice Lacking Leptimentioning

confidence: 99%

Body temperature as a mouse pharmacodynamic response to bombesin receptor subtype-3 agonists and other potential obesity treatments

Metzger¹,

Gagen²,

Raustad³

et al. 2010

American Journal of Physiology-Endocrinology and Metabolism

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Lanza T, Lin LS, Nargund RP, Guan XM, Strack AM, Reitman ML. Body temperature as a mouse pharmacodynamic response to bombesin receptor subtype-3 agonists and other potential obesity treatments. Am J Physiol Endocrinol Metab 299: E816 -E824, 2010. First published August 31, 2010; doi:10.1152/ajpendo.00404.2010.-Treatment of rodents with a bombesin receptor subtype-3 (BRS-3) agonist reduces food intake and increases fasting metabolic rate, causing weight loss with continued treatment. In small mammals, core body temperature (Tb) is regulated in part by nutritional status, with a reduced Tb during fasting. We report that fed Brs3 knockout mice have a lower T b, which is discordant with their nutritional status. Treatment of wild-type mice with a BRS-3 agonist increased Tb, more so when the baseline Tb was reduced such as by fasting or during the inactive phase of the light cycle. With repeated BRS-3 agonist dosing, the Tb increase attenuated despite continued weight loss efficacy. The increase in T b was not prevented by inhibitors of prostaglandin E (PGE) production but was partially reduced by a ␤-adrenergic blocker. These results demonstrate that BRS-3 has a role in body temperature regulation, presumably secondary to its effect on energy metabolism, including effects on sympathetic tone. By making use of this phenomenon, the reversal of the fasting Tb reduction was developed into a sensitive single-dose pharmacodynamic assay for BRS-3 agonism and other antiobesity compounds acting by various mechanisms, including sibutramine, cannabinoid-1, and melanin-concentrating hormone-1 receptor blockers, and melanocortin, ␤3-adrenergic, and cholecystokinin-1 receptor agonists. These drugs increased both the fasted Tb and the fasted, resting metabolic rates. The Tb assay is a robust, information-rich assay that is simpler and has a greater throughput than measuring metabolic rate and is a practical, effective tool for drug discovery. tachyphylaxis; metabolic rate; thermoregulation; fasting; drug discovery MAMMALS ARE HOMEOTHERMS, regulating their core body temperature (T b ) within a narrow range (30). T b impacts all facets of life, ranging from chemical reaction rates to defense against infection. Mammals typically live in environments below their thermoneutral range, so maintenance of T b involves generating and conserving heat. Heat is generated as a byproduct of metabolic processes and via dedicated heat generation ("facultative thermogenesis") that occurs principally in brown adipose tissue, a specialized tissue whose only known function is efficient heat generation (5). Heat is conserved through a variety of mechanisms, including behavioral (nests, huddling, choice of warm environment), anatomic (fur, increased body size), and physiological (vasoconstriction, regulation of energy expenditure) mechanisms (11).Small mammals maintain their T b , despite their increased heat loss to the environment, by burning a significant fraction of their energy intake for warmth. For example, about one-third of the food intake is ...

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Spiropiperidines

2018

Privileged Structures in Drug Discovery

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Synthesis and SAR of potent and orally bioavailable tert-butylpyrrolidine archetype derived melanocortin subtype-4 receptor modulators

Cited by 16 publications

References 15 publications

Bench-top to clinical therapies: A review of melanocortin ligands from 1954 to 2016

Bench-top to clinical therapies: A review of melanocortin ligands from 1954 to 2016

Body temperature as a mouse pharmacodynamic response to bombesin receptor subtype-3 agonists and other potential obesity treatments

Spiropiperidines

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