Gary Mark Coppola

Chapter 19. DPP-IV inhibition and therapeutic potential

Publisher Summary This chapter elaborates the dipeptidyl peptidase IV (DPP-IV) inhibition and therapeutic potential. DPP-IVs structural characteristics, proteolytic substrate requirements, and the profile of key and new inhibitors of its catalytic function are presented. With a half-life of more than 96 hours, DPP-IV is constitutively expressed by a variety of cell types, particularly on differentiated epithelial cells of the intestine, liver, prostate tissue, corpus luteum, and kidney proximal tubules as well as leukocyte subsets, such as T-helper lymphocytes and subsets of macrophages. The DPP-IV gene and its associated cDNAs from human, mouse, and rat tissue have been cloned. A single gene encoding DPP-IV has been localized to human chromosome 2 and encodes two mRNA species sized at approximately 2.8 and 4.2 kb that are present in most tissues producing DPP-IV. GLP-1 stimulates glucose-dependent insulin secretion, inhibits glucagon release, slows gastric emptying, promotes growth and differentiation of p-cells, and stimulates insulin gene expression and biosynthesis. The in vitro and in vivo studies in mice, rats, and humans have shown that DPP-IV is the primary inactivation pathway for the intestinal growth factor, GLP-2.

A new scavenger resin for amines

Isatoic anhydride (1) can be attached to Merrifield resin by alkylation on its nitrogen. A maximum loading of 3.2 mmol of anhydride/g of 5 was achieved. This resin, due to the highly reactive anhydride moiety, completely removes primary and secondary aliphatic amines from reactions where they are used in excess.

1-Aminomethylisoquinoline-4-carboxylates as novel dipeptidylpeptidase IV inhibitors

Structure-activity relationship within a series of 1-aminoalkylisoquinoline-4-carboxylates as inhibitors of DPP-IV is described. A primary aminomethyl group is required to maintain biological activity. Substitution of the isoquinoline at the 6- and 8-positions with methoxy groups increases potency to 53 times that of the lead compound SDZ 029-576.

N-Hydroxyphthalimide/Cobalt Acetate, a New Catalytic Oxidative System for the Synthesis of Benzimidazoles

Abstract Benzimidazoles are readily prepared from 1,2-phenylenediamine and an aldehyde using air and catalytic N-hydroxyphthalimide/Co(OAc)2 as the oxidant. Both electron-donating and electron-withdrawing groups are tolerated.

Thiourea-based gemfibrozil analogues as HDL-elevating agents.

A series of gemfibrozil analogues with a thiourea moiety embedded in the side chain was prepared and evaluated as HDL-elevating agents. Derivatives 8b, 9b, 9c, and 9d were found to be approximately as effective as gemfibrozil (1) for HDL cholesterol elevation.

A CONVENIENT PREPARATION OF FARNESYLAMINE

Abstract The efficient synthesis of farnesylamine (1) was accomplished by two separate routes. The first, by the alkylation of triflouroacetamide with farnesyl bromide followed by base hydrolysis. The second, by displacement of the halogen of farnesyl bromide with lithium bis(trimethylsilyl) amide followed by methanolysis.

Cyclization of 4‐Hydroxy‐3‐hydroxyalkylcarbostyrils Under Mitsunobu Conditions

Abstract Reaction of 4‐hydroxy‐3‐hydroxyalkyl‐1‐methyl‐2(1H)quinolinones with Ph3P/DEAD gives either C‐ or O‐cyclized products depending on chain length. Hydroxyethyl produces only spiro cyclopropylquinolinone 6, whereas hydroxypropyl affords only pyranoquinolinone 8. Hydroxybutyl gives a 2:1 mixture of spiro cyclopentylquinolinone 11 and oxepinoquinolinone 10.

A reliable, high-yielding preparation of 2,6 -dimethyl -4-hydroxybenzaldehyde

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Facile Synthesis of 1,2-Dialkyl-3-Phenyl-4-Quinolinones

Abstract The synthesis of 1,2-dialkyl-3-phenyl-4-quinolinones (1) is readily accomplished by a low-temperature reaction of an N-alkylisatoic anhydride with the therraodynamic potassium enolate of phenyl-acetone. The reaction has also been extended to encompass the synthesis of the more complex 2-(3-hydroxy-propyl)-3-(4-fluorophenyl)-1-methyl-4(1H)-quinolinone (10).

An Efficient Synthesis of Arboricine

Abstract The synthesis of 4-hydroxy-1-methyl-3-phenyl-2(1H)-quinolinone (arboricine) was accomplished in 80% yield from the reaction of N-methylisatoic anhydride with the potassium enolate of ethyl phenyl-acetate.