DPP-4 (dipeptidyl peptidase-4) degrades the incretin hormones GLP-1 (glucagon-like peptide-1) and GIP (gastric inhibitory polypeptide), decreasing their stimulatory effects on beta-cell insulin secretion. In patients with Type 2 diabetes, meal-related GLP-1 secretion is reduced. DPP-4 inhibitors (alogliptin, saxagliptin, sitagliptin and vildagliptin) correct the GLP-1 deficiency by blocking this degradation, prolonging the incretin effect and enhancing glucose homoeostasis. DPP-4 is a member of a family of ubiquitous atypical serine proteases with many physiological functions beyond incretin degradation, including effects on the endocrine and immune systems. The role of DPP-4 on the immune system relates to its extra-enzymatic activities. The intracytosolic enzymes DPP-8 and DPP-9 are recently discovered DPP-4 family members. Although specific functions of DPP-8 and DPP-9 are unclear, a potential for adverse effects associated with DPP-8 and DPP-9 inhibition by non-selective DPP inhibitors has been posed based on a single adverse preclinical study. However, the preponderance of data suggests that such DPP-8 and DPP-9 enzyme inhibition is probably without clinical consequence. This review examines the structure and function of the DPP-4 family, associated DPP-4 inhibitor selectivity and the implications of DPP-4 inhibition in the treatment of Type 2 diabetes.
The effect of zinc iodide on the catalytic, enantioselective cyclopropanation of allylic alcohols is examined with bis(iodomethyl)zinc as the reagent and bis-methanesulfonamide 7 as the catalyst. Significant rate enhancement was observed when 1 equiv of zinc iodide was present, but more importantly, the enantiomeric excess of the product cyclopropane increased from 80% to 89% for the substrate cinnamyl alcohol. Reaction studies and spectroscopic investigations show that this remarkable influence is the result of reagent modification via a Schlenk equilibrium that produces the more reactive and selective species (iodomethyl)zinc iodide.
Catalytic, enantioselective cyclopropanation of a broad range of allylic alcohols and one homoallylic alcohol was carried out. The cyclopropanation reagent employed was bis(iodomethyl)zinc generated by the method of Furukawa, and the chiral promoter used (10 mol %) was the N,N-bis(methanesulfonyl) derivative of (R,R)-1,2-diaminocyclohexane. Three experimental features were found to be critical for the rapid and selective cyclopropanation: (1) use of the ethylzinc alkoxide of the allylic alcohol as the substrate by prior deprotonation of the allylic alcohols by diethylzinc, (2) the formation of the zinc complex of the promoter by prior deprotonation of the bis-sulfonamide with diethylzinc, and (3) the use of added zinc iodide generated in situ from diethylzinc and iodine. The stereoselectivity of cyclopropanation was found to be independent of olefin geometry and worked well for substrates bearing both aliphatic and aromatic substituents at either or both 3-positions of the allylic alcohol. However, a methyl substituent on the 2-position of the allyl alcohol was not well tolerated and led to slow reactions and poor enantioselectivities. A rationale for the observed selectivities is proposed.
Continued structure-activity relationship (SAR) exploration within our previously disclosed azolopyrimidine containing dipeptidyl peptidase-4 (DPP4) inhibitors led us to focus on an imidazolopyrimidine series in particular. Further study revealed that by replacing the aryl substitution on the imidazole ring with a more polar carboxylic ester or amide, these compounds displayed not only increased DPP4 binding activity but also significantly reduced human ether-a-go-go related gene (hERG) and sodium channel inhibitory activities. Additional incremental adjustment of polarity led to permeable molecules which exhibited favorable pharmacokinetic (PK) profiles in preclinical animal species. The active site binding mode of these compounds was determined by X-ray crystallography as exemplified by amide 24c. A subsequent lead molecule from this series, (+)-6-(aminomethyl)-5-(2,4-dichlorophenyl)-N-(1-ethyl-1H-pyrazol-5-yl)-7-methylimidazo[1,2-a]pyrimidine-2-carboxamide (24s), emerged as a potent, selective DPP4 inhibitor that displayed excellent PK profiles and in vivo efficacy in ob/ob mice.
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