Pyrrolidides: synthesis and structure-activity relationship as inhibitors of dipeptidyl peptidase IV

doi:10.1016/S0223-5234(97)89082-4

European Journal of Medicinal Chemistry

Volume 32, Issue 4, 1997, Pages 301-309

https://doi.org/10.1016/S0223-5234(97)89082-4 Get rights and content

Summary

Dipeptidyl peptidase IV cleaves specifically the peptide bond at the carboxyl side of a proline at the penultimate N-terminal position of a peptide. It is thought to be important for the regulation of biologically active peptides. Moreover, it has been identified as an activation marker of T-lymphocytes (CD26). Pyrrolidides and thiazolidides are known as reversible inhibitors of DPP IV. Several homologues, unsaturated, open and 3-substituted analogues were synthesized in order to determine the structure-activity relationship of the P-1 site. l-Isoleucine was taken as P-2 amino acid. 1-(l-Isoleucyl)-3(S)-fluoropyrrolidine is about as active as the non-fluorinated compound and behaves as a competitive inhibitor. Other changes decrease or abolish the activity.

References (21)

BarrettAJ et al.
Arch Biochem Biophys
(1995)
TiruppathiC et al.
J Biol Chem
(1990)
MedeirosMS et al.
Biochimie
(1994)
HoffmannT et al.
FEBS Lett
(1993)
LambeirAM et al.
Biochim Biophys Acta
(1996)
LiJ et al.
Arch Biochem Biophys
(1995)
De MeesterI et al.
J Immunol Methods
(1996)
Duke-CohanJS et al.
J Biol Chem
(1995)
YaronA et al.
Crit Rev Biochem Mol Biol
(1993)
FrohmanLA et al.
J Clin Invest
(1986)

There are more references available in the full text version of this article.

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Dipeptidyl peptidase-4 (DPP-4) is one of the widely explored novel targets for Type 2 diabetes mellitus (T2DM) currently. Research has been focused on the strategy to preserve the endogenous glucagon like peptide (GLP)-1 activity by inhibiting the DPP-4 action. The DPP-4 inhibitors are weight neutral, well tolerated and give better glycaemic control over a longer duration of time compared to existing conventional therapies. The journey of DPP-4 inhibitors in the market started from the launch of sitagliptin in 2006 to latest drug teneligliptin in 2012. This review is mainly focusing on the recent medicinal aspects and advancements in the designing of DPP-4 inhibitors with the therapeutic potential of DPP-4 as a target to convey more clarity in the diffused data.
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A series of N-acylated glycyl-(2-cyano)pyrrolidines were synthesized with the aim of generating structure–activity relationship (SAR) data for this class of compounds as inhibitors of fibroblast activation protein (FAP). Specifically, the influence of (1) the choice of the N-acyl group and (2) structural modification of the 2-cyanopyrrolidine residue were investigated. The inhibitors displayed inhibitory potency in the micromolar to nanomolar range and showed good to excellent selectivity with respect to the proline selective dipeptidyl peptidases (DPPs) DPP IV, DPP9 and DPP II. Additionally, selectivity for FAP with respect to prolyl oligopeptidase (PREP) is reported. Not unexpectedly, the latter data suggest significant overlap in the pharmacophoric features that define FAP or PREP-inhibitory activity and underscore the importance of systematically evaluating the FAP/PREP-selectivity index for inhibitors of either of these two enzymes. Finally, this study forwards several compounds that can serve as leads or prototypic structures for future FAP-selective-inhibitor discovery.
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Following this, an investigation of P1 replacements was undertaken and fluoropyrrolidides were prepared [106]. Fluoropyrrolidides had been shown earlier to function as DPPIV inhibitors [107]. To summarize, the (3S,4S)- and (3R,4R)-3,4-difluoropyrrolidides were found to decrease potency while the 3,3-difluoropyrrolidides exhibited potencies similar to their thiazolidide counterparts.
Dipeptidyl Peptidase IV (DPPIV) is a post-proline cleaving serine protease with a catalytic triad of Ser-Asp-His inversely oriented to classical serine proteases and with significant homology to other α, β-hydroxylases. DPPIV is expressed as a 110 kDa glycoprotein on the surface of cells of most tissues, including kidney, liver, intestine, placenta, prostate, skin, lymphocytes, and endothelial cells. DPPIV is catalytically active as a dimer. Proteolytic cleavage of DPPIV from cell surfaces results in a soluble circulating form with a monomeric mass of approximately 100 kDa. In addition to cleaving glucagon-like peptide-1, DPPIV may play a role in the cleavage of other substrates with accessible amino-terminal Xaa-Pro- or Xaa-Ala-dipeptide sequences, resulting in their inactivation or alteration in their biological activities. Potential DPPIV substrates include growth hormone releasing hormone; glucose-dependent insulinotropic polypeptide; pituitary adenylate cyclase-activating polypeptide 38; substance P; bradykinin; gastrin releasing peptide; neuropeptide Y; peptide YY; certain chemokines, such as regulated on activation normal T cell expressed and secreted; stromal cell-derived factor; and eotaxin and macrophage-derived chemokines.
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Two issues with this series are chemical stability (the compounds cyclize to give inactive boron amides [149, 150]) and selectivity [151, 152]. Acylthiazolidides and acylpyrrolidides are further examples of substrate mimetics [153, 154]. Compound (51), P32/98, has been tested in the clinic and it shows efficacy in improving glucose tolerance in diabetic patients [155].
The identification of high-quality leads has become an important part of the process of drug discovery. The process of lead identification has been formalized to a greater or lesser extent in different companies, and publications have started to appear describing the various strategies that have been implemented. However, the practice in the medicinal chemistry literature still reflects the historical focus on potency. It has been pointed out that the historical focus on potency in the early stages of drug discovery has given way to a more balanced process, where additional factors, such as physicochemical properties, pharmacokinetics, and even safety, are addressed before significant resources are committed to a chemical series.
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Pyrrolidides: synthesis and structure-activity relationship as inhibitors of dipeptidyl peptidase IV

Summary

Arch Biochem Biophys

J Biol Chem

Biochimie

FEBS Lett

Biochim Biophys Acta

Arch Biochem Biophys

J Immunol Methods

J Biol Chem

Crit Rev Biochem Mol Biol

J Clin Invest