Longenecker KL

References (3)

Title : Discovery of 2-[4-{{2-(2S,5R)-2-cyano-5-ethynyl-1-pyrrolidinyl]-2-oxoethyl]amino]- 4-methyl-1-piperidinyl]-4-pyridinecarboxylic acid (ABT-279): a very potent, selective, effective, and well-tolerated inhibitor of dipeptidyl peptidase-IV, useful for the treatment of diabetes - Madar_2006_J.Med.Chem_49_6416
Author(s) : Madar DJ , Kopecka H , Pireh D , Yong H , Pei Z , Li X , Wiedeman PE , Djuric SW , von Geldern TW , Fickes MG , Bhagavatula L , McDermott T , Wittenberger S , Richards SJ , Longenecker KL , Stewart KD , Lubben TH , Ballaron SJ , Stashko MA , Long MA , Wells H , Zinker BA , Mika AK , Beno DW , Kempf-Grote AJ , Polakowski J , Segreti J , Reinhart GA , Fryer RM , Sham HL , Trevillyan JM
Ref : Journal of Medicinal Chemistry , 49 :6416 , 2006
Abstract : Dipeptidyl peptidase-IV (DPP-IV) inhibitors are poised to be the next major drug class for the treatment of type 2 diabetes. Structure-activity studies of substitutions at the C5 position of the 2-cyanopyrrolidide warhead led to the discovery of potent inhibitors of DPP-IV that lack activity against DPP8 and DPP9. Further modification led to an extremely potent (Ki(DPP)(-)(IV) = 1.0 nM) and selective (Ki(DPP8) > 30 microM; Ki(DPP9) > 30 microM) clinical candidate, ABT-279, that is orally available, efficacious, and remarkably safe in preclinical safety studies.
ESTHER : Madar_2006_J.Med.Chem_49_6416
PubMedSearch : Madar_2006_J.Med.Chem_49_6416
PubMedID: 17034148
Gene_locus related to this paper: human-DPP4

Title : Xanthine mimetics as potent dipeptidyl peptidase IV inhibitors - Kurukulasuriya_2006_Bioorg.Med.Chem.Lett_16_6226
Author(s) : Kurukulasuriya R , Rohde JJ , Szczepankiewicz BG , Basha F , Lai C , Jae HS , Winn M , Stewart KD , Longenecker KL , Lubben TW , Ballaron SJ , Sham HL , von Geldern TW
Ref : Bioorganic & Medicinal Chemistry Lett , 16 :6226 , 2006
Abstract : A series of xanthine mimetics containing 5,5 and 5,6 heterocycle fused imidazoles were synthesized as dipeptidyl peptidase IV inhibitors. Compound 7 is potent (h-DPPIV K(i)=2nM) and exhibits excellent selectivity and no species specificity against rat and human enzymes. The X-ray structure confirms that the binding mode of 7 to rat DPPIV is similar to the parent xanthines.
ESTHER : Kurukulasuriya_2006_Bioorg.Med.Chem.Lett_16_6226
PubMedSearch : Kurukulasuriya_2006_Bioorg.Med.Chem.Lett_16_6226
PubMedID: 17010607
Gene_locus related to this paper: ratno-dpp4

Title : Crystal structures of DPP-IV (CD26) from rat kidney exhibit flexible accommodation of peptidase-selective inhibitors - Longenecker_2006_Biochemistry_45_7474
Author(s) : Longenecker KL , Stewart KD , Madar DJ , Jakob CG , Fry EH , Wilk S , Lin CW , Ballaron SJ , Stashko MA , Lubben TH , Yong H , Pireh D , Pei Z , Basha F , Wiedeman PE , von Geldern TW , Trevillyan JM , Stoll VS
Ref : Biochemistry , 45 :7474 , 2006
Abstract : Dipeptidyl peptidase IV (DPP-IV) belongs to a family of serine peptidases, and due to its indirect regulatory role in plasma glucose modulation, DPP-IV has become an attractive pharmaceutical target for diabetes therapy. DPP-IV inactivates the glucagon-like peptide (GLP-1) and several other naturally produced bioactive peptides that contain preferentially a proline or alanine residue in the second amino acid sequence position by cleaving the N-terminal dipeptide. To elucidate the details of the active site for structure-based drug design, we crystallized a natural source preparation of DPP-IV isolated from rat kidney and determined its three-dimensional structure using X-ray diffraction techniques. With a high degree of similarity to structures of human DPP-IV, the active site architecture provides important details for the design of inhibitory compounds, and structures of inhibitor-protein complexes offer detailed insight into three-dimensional structure-activity relationships that include a conformational change of Tyr548. Such accommodation is exemplified by the response to chemical substitution on 2-cyanopyrrolidine inhibitors at the 5 position, which conveys inhibitory selectivity for DPP-IV over closely related homologues. A similar conformational change is also observed in the complex with an unrelated synthetic inhibitor containing a xanthine core that is also selective for DPP-IV. These results suggest the conformational flexibility of Tyr548 is unique among protein family members and may be utilized in drug design to achieve peptidase selectivity.
ESTHER : Longenecker_2006_Biochemistry_45_7474
PubMedSearch : Longenecker_2006_Biochemistry_45_7474
PubMedID: 16768443
Gene_locus related to this paper: ratno-dpp4