Discovery of diamide compounds as diacylglycerol acyltransferase 1 (DGAT1) inhibitors

Nakajima, Katsumasa; April, Myriam; Brewer, Jason; Daniels, Thomas; Forster, Cornelia; Gilmore, Thomas A.; Jain, Mohit; Kanter, Aaron; Kwak, Young‐Shin; Li, Jingzhou; McQuire, Les; Serrano‐Wu, Michael H.; Streeper, Ryan S.; Szklennik, Paul V.; Thompson, James; Wang, Bing

doi:10.1016/j.bmcl.2016.01.025

Cited by 4 publications

(2 citation statements)

References 16 publications

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“…Replacement of Phe in enkephalin analogs provided 2-fold enhancement of morphine-like activity. 137 Dipeptide antagonists of substance P with specificity for the NK-1 receptor were prepared with a number of unnatural aromatic amino acids, such as 3-(6-methyl-2-naphthyl)-Ala, 3-(6-chloro-2-naphthyl)-Ala, 3-(5,6,7,8-tetrahydro-2-naphthyl)-Ala (188), and 3-(2,3-dihydro-1,4-benzodioxin-6-yl)-Ala (189), 149 or with a number of conformationally restricted 193), (E)-dehydro-Phe (194), and (Z)-dehydro-Phe (195)). 150 Tic (196) is commonly used as a conformationally restricted replacement for Phe, reducing the movement of the aromatic ring as well as the peptide backbone.…”

Section: Journal Of Medicinal Chemistrymentioning

confidence: 99%

“…N -Methylation is one common approach that introduces conformational constraints which can significantly affect ligand potency and receptor subtype selectivity . A peptide to peptidomimetic transformation is nicely illustrated in a recent paper from Novartis (Scheme ), in which a tripeptide-like diacylglycerol acyltransferases (DGAT1) inhibitor 241 (DGAT1 IC 50 = 0.007 μM, but not bioavailable or efficacious when dosed orally to rats) was first C -terminal modified ( 242 ), then N -terminal modified ( 243 ), and then further derivatized to produce 245 , with IC 50 = 0.062 μM, improved solubility, gut permeability and metabolic stability, high oral bioavailability (76%), and oral efficacy . Attempts to remove the central amino acid residue produced an inactive compound 244 .…”

Section: Unusual Amino Acids In Drugsmentioning

confidence: 99%

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Unusual Amino Acids in Medicinal Chemistry

2016

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Unusual amino acids are fundamental building blocks of modern medicinal chemistry. The combination of readily functionalized amine and carboxyl groups attached to a chiral central core along with one or two potentially diverse side chains provides a unique three-dimensional structure with a high degree of functionality. This makes them invaluable as starting materials for syntheses of complex molecules, highly diverse elements for SAR campaigns, integral components of peptidomimetic drugs, and potential drugs on their own. This Perspective highlights the diversity of unnatural amino acid structures found in hit-to-lead and lead optimization campaigns and clinical stage and approved drugs, reflecting their increasingly important role in medicinal chemistry.

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Section: Journal Of Medicinal Chemistrymentioning

confidence: 99%

Section: Unusual Amino Acids In Drugsmentioning

confidence: 99%

Unusual Amino Acids in Medicinal Chemistry

2016

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Discovery of novel DGAT1 inhibitors by combination of machine learning methods, pharmacophore model and 3D-QSAR model

et al. 2021

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Facile ring opening reaction of oxazolone enables efficient amidation for aminoisobutyric acid

Won

Lee

et al. 2018

Arch. Pharm. Res.

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4,4-Dimethyloxazolones derived from N-protected aminoisobutyric acid (AIB) are particularly known as poor electrophiles due to the steric hindrance around the carbonyl and not employed as useful intermediates for amidation whereas numerous examples have been reported to support the utility of other oxazolones in amidation. AIB is an important and strategical synthon in medicinal chemistry but the peptide bond formation of the N-protected urethane derivatives of AIB is known to be often unproductive due to the rapid formation of the stable 4,4-dimethyloxazolone via an intramolecular cyclization. We discovered that the 4,4-dimethyloxazolone of an AIB urethane is in fact an excellent electrophile that enables efficient amidation even with weakly reactive nucleophiles. The 4,4-dimethyloxazolone can be stored in a pure form and used as a reagent offering an efficient and convenient synthetic tool for generating AIB-peptide analogs.

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Discovery of diamide compounds as diacylglycerol acyltransferase 1 (DGAT1) inhibitors

Cited by 4 publications

References 16 publications

Unusual Amino Acids in Medicinal Chemistry

Unusual Amino Acids in Medicinal Chemistry

Discovery of novel DGAT1 inhibitors by combination of machine learning methods, pharmacophore model and 3D-QSAR model

Facile ring opening reaction of oxazolone enables efficient amidation for aminoisobutyric acid

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