Potent non-nitrile dipeptidic dipeptidyl peptidase IV inhibitors

Simpkins, Ligaya M.; Bolton, Scott A.; Pi, Zulan; Sutton, James; Kwon, Chet; Zhao, Guohua; Magnin, David R.; Augeri, David J.; Güngör, Timur; Rotella, David P.; Sun, Zhong; Liu, Yajun; Slusarchyk, William S.; Marcinkeviciene, Jovita; Robertson, James G.; Wang, Aiying; Robl, Jeffrey A.; Atwal, Karnail S.; Zahler, Robert; Parker, Rex A.; Kirby, Mark; Hamann, Lawrence G.

doi:10.1016/j.bmcl.2007.09.090

Cited by 26 publications

(17 citation statements)

References 30 publications

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“…Methanopyrrolidine 363 (BMS-538305) was reported as one such compound (K i = (10 ± 3) nM). 677 Mechanistic studies suggest a two-step binding mode of the cyanopyrrolidines by first forming an initial encounter complex, whereupon a covalently bound intermediate with strong enzyme-inhibitor H-bonds forms. 678 Active site mutants of recombinant DPP-IV co-crystallized with inhibitors further supported this mechanism of action (Figure 5).…”

Section: Miscellaneous Non-cns Targetsmentioning

confidence: 99%

The Lipophilic Bullet Hits the Targets: Medicinal Chemistry of Adamantane Derivatives

Wanka¹,

Iqbal²,

Schreiner³

2013

Chem. Rev.

580

475

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Section: Miscellaneous Non-cns Targetsmentioning

confidence: 99%

The Lipophilic Bullet Hits the Targets: Medicinal Chemistry of Adamantane Derivatives

Wanka¹,

Iqbal²,

Schreiner³

2013

Chem. Rev.

580

475

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“…Similarly, using alkyl iodide homolysis to give α-heteroatom-bearing radicals can be complicated by the presence of neighboring oxygen, nitrogen, and sulfur atoms. Thus, the unstable iodocarbamate 110 ( 70 ) can readily eliminate to give olefin 111 . Additionally, using this method to generate α-iodo and α-bromo radicals can lead to chemoselectivity issues, as in the case of geminal dihalides 112 and 113 .…”

Section: Functionalized Olefin Cross-couplingmentioning

confidence: 99%

Fe-Catalyzed C–C Bond Construction from Olefins via Radicals

et al. 2017

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This Article details the development of the iron-catalyzed conversion of olefins to radicals and their subsequent use in the construction of C–C bonds. Optimization of a reductive diene cyclization led to the development of an intermolecular cross-coupling of electronically-differentiated donor and acceptor olefins. Although the substitution on the donor olefins was initially limited to alkyl and aryl groups, additional efforts culminated in the expansion of the scope of the substitution to various heteroatom-based functionalities, providing a unified olefin reactivity. A vinyl sulfone acceptor olefin was developed, which allowed for the efficient synthesis of sulfone adducts that could be used as branch points for further diversification. Moreover, this reactivity was extended into an olefin-based Minisci reaction to functionalize heterocyclic scaffolds. Finally, mechanistic studies resulted in a more thorough understanding of the reaction, giving rise to the development of a more efficient second-generation set of olefin cross-coupling conditions.

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“…Both 10 and 30 mg/kg of 21s produced reductions in HOMA-IR (Figure C, P < 0.05), indicating that both doses of 21s produced an improvement in insulin sensitivity. A DPP4 inhibitor BMS-538305 (10 mg/kg, p.o., b.i.d ) was used for comparison . In the study shown in Figure , 10 mg/kg and 30 mg/kg b.i.d .…”

Section: Resultsmentioning

confidence: 99%

“…Effect on fasting (A) glucose and (B) insulin levels and (C) HOMA-IR following multiple-dose treatment of 21s in DIO mice. BMS-538305 is an internal DPP4 inhibitor …”

Section: Resultsmentioning

confidence: 99%

Screening Hit to Clinical Candidate: Discovery of BMS-963272, a Potent, Selective MGAT2 Inhibitor for the Treatment of Metabolic Disorders

et al. 2021

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MGAT2 inhibition is a potential therapeutic approach for the treatment of metabolic disorders. High-throughput screening of the BMS internal compound collection identified the aryl dihydropyridinone compound 1 (hMGAT2 IC50 = 175 nM) as a hit. Compound 1 had moderate potency against human MGAT2, was inactive vs mouse MGAT2 and had poor microsomal metabolic stability. A novel chemistry route was developed to synthesize aryl dihydropyridinone analogs to explore structure–activity relationship around this hit, leading to the discovery of potent and selective MGAT2 inhibitors 21f, 21s, and 28e that are stable to liver microsomal metabolism. After triaging out 21f due to its inferior in vivo potency, pharmacokinetics, and structure-based liabilities and tetrazole 28e due to its inferior channel liability profile, 21s (BMS-963272) was selected as the clinical candidate following demonstration of on-target weight loss efficacy in the diet-induced obese mouse model and an acceptable safety and tolerability profile in multiple preclinical species.

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Potent non-nitrile dipeptidic dipeptidyl peptidase IV inhibitors

Cited by 26 publications

References 30 publications

The Lipophilic Bullet Hits the Targets: Medicinal Chemistry of Adamantane Derivatives

The Lipophilic Bullet Hits the Targets: Medicinal Chemistry of Adamantane Derivatives

Fe-Catalyzed C–C Bond Construction from Olefins via Radicals

Screening Hit to Clinical Candidate: Discovery of BMS-963272, a Potent, Selective MGAT2 Inhibitor for the Treatment of Metabolic Disorders

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