Fluoroolefins as amide bond mimics in dipeptidyl peptidase IV inhibitors (original) (raw)
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Navigating the chemical space of dipeptidyl peptidase-4 inhibitors
Drug Design, Development and Therapy, 2015
Drug Design, Development and Therapy Dovepress submit your manuscript | www.dovepress.com Dovepress 4515 O r i g i n a l r e s e a r c h open access to scientific and medical research Open access Full Text article http://dx.
ChemInform, 1999
In this review the structural and functional aspects of dipeptidyl peptidase IV (DPP IV) will be described, and the therapeutic potential of DPP IV inhibitors will be highlighted. DPP IV will be situated in clan SC, a group of serine proteases that contains several proline specific peptidases. Structural aspects of DPP IV and its interaction with different types of inhibitors are recently revealed by the publication of several crystal structures. Especially the design and development of new DPP IV inhibitors based on the threedimensional structure, substrate specificity and catalytic mechanism will be discussed. In the last years there was an important development of new pyrrolidine-2-nitriles with very promising therapeutic properties for the treatment of type 2 diabetes. The role of DPP IV in peptide metabolism of members of the PACAP/glucagon peptide family, neuropeptides and chemokines has been thoroughly investigated during recent years. This is directly related to the promising therapeutic potential of DPP IV inhibitors in the treatment of type 2 diabetes and in the treatment of immunological disorders. Several inhibitors are currently under investigation in clinical trials for the treatment of type 2 diabetes and represent a new class of drugs for the treatment of this disease.
Journal of Applied Pharmaceutical Science, 2018
Research on the quantitative structure-activity relationship (QSAR) of the 4-fluoropyrrolidine-2-carbonitrile and octahydrocyclopenta[b]pyrrole-2-carbonitrile as dipeptidyl peptidase IV (DPP4) inhibitor was performed. The molecular descriptors were calculated and the best QSAR model was developed, which satisfied statistical parameters such as correlation coefficient R = 0.912 and leave-one-out validation coefficients q 2 = 0.608. The predictive quality of the model was tested against test set compounds with R 2pred value of 0.7057. A novel compound (ND1) was designed and its predicted IC 50 was predicted, which was lower compared with that of the parent compound (S24). Molecular docking and molecular dynamics simulation of 40 ns showed the stability of binding orientation of ND1, the parent compound, and native ligand of DPP4. Prediction of affinity using molecular mechanics/Poisson-Boltzmann/surface area method revealed that the ND1 has a comparable affinity with the parent and natural ligands.
Discovery of potent and selective β-homophenylalanine based dipeptidyl peptidase IV inhibitors
Bioorganic & Medicinal Chemistry Letters, 2004
Modification of in-house screening lead β-aminoacyl proline 8 gave an equipotent thiazolidide 9. Extensive SAR studies on the phenyl ring of 9 led to the discovery of a novel series of potent and selective DP-IV inhibitors. Introduction of a fluorine at the 2-position proved to be crucial for the potency of this series. The 2,5-difluoro (22q) and 2,4,5-trifluoro (22t) analogues were potent inhibitors of DP-IV (IC50 = 270, 119 nM, respectively).
Journal of Medicinal Chemistry, 2003
In this paper we report the systematic search for new, potent, and selective DPP II inhibitors. A study of the structure-activity relationship was conducted starting from aminoacyl pyrrolidides as lead compounds. Rational exploration of the P 1 and P 2 building blocks led to the discovery of some very potent DPP II inhibitors which can be characterized by their high selectivity for DPP II with regard to DPP IV. Dab-Pip and Dab-Pip-2-CN were selected as the most promising inhibitors (IC 50 nM range) and
Development of potent and selective dipeptidyl peptidase II inhibitors
Bioorganic & Medicinal Chemistry Letters, 2002
Structure-activity investigations of product-like dipeptide analogues lacking the C-terminal carbonyl function resulted in potent and selective dipeptidyl peptidase II (DPP II) inhibitors. Dab-Pip has an IC 50 =0.13 mM for DPP II and a 7600-fold selectivity with respect to DPP IV. This compound will be highly valuable for the investigation of the biochemical function of DPP II. #
Dipeptidyl Peptidase-4 Inhibition: Linking Chemical Properties to Clinical Safety
Current Medicinal Chemistry, 2011
The new drug class of dipeptidyl peptidase-4 (DPP4) inhibitors has been widely accepted in the daily management of type 2 diabetes since its strategic advantages with regard to body weight, risk of hypoglycaemia, and beta cell survival. We have previously evaluated the theoretical implications of DPP4 inhibition given that the enzyme is involved in regulating biological activity of hormones, neuropeptides, and cytokines. We intend now 1) to provide a critical appraisal of safety and tolerability as they emerged from the available clinical studies, and 2) to establish, if possible, a relation between chemical properties, biological activity, and the observed side effects in vivo.