Rohde JJ

References (2)

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 : Discovery of 3-methyl-N-(1-oxy-3',4',5',6'-tetrahydro-2'H-[2,4'-bipyridine]-1'-ylmethyl)benzam ide (ABT-670), an orally bioavailable dopamine D4 agonist for the treatment of erectile dysfunction - Patel_2006_J.Med.Chem_49_7450
Author(s) : Patel MV , Kolasa T , Mortell K , Matulenko MA , Hakeem AA , Rohde JJ , Nelson SL , Cowart MD , Nakane M , Miller LN , Uchic ME , Terranova MA , El-Kouhen OF , Donnelly-Roberts D , Namovic MT , Hollingsworth PR , Chang R , Martino BR , Wetter JM , Marsh KC , Martin R , Darbyshire JF , Gintant G , Hsieh GC , Moreland RB , Sullivan JP , Brioni JD , Stewart AO
Ref : Journal of Medicinal Chemistry , 49 :7450 , 2006
Abstract : The goal of this study was to identify a structurally distinct D(4)-selective agonist with superior oral bioavailability to our first-generation clinical candidate 1a (ABT-724) for the potential treatment of erectile dysfunction. Arylpiperazines such as (heteroarylmethyl)piperazine 1a, benzamide 2, and acetamides such as 3a,b exhibit poor oral bioavailability. Structure-activity relationship (SAR) studies with the arylpiperidine template provided potent partial agonists such as 4d and 5k that demonstrated no improvement in oral bioavailability. Further optimization with the (N-oxy-2-pyridinyl)piperidine template led to the discovery of compound 6b (ABT-670), which exhibited excellent oral bioavailability in rat, dog, and monkey (68%, 85%, and 91%, respectively) with comparable efficacy, safety, and tolerability to 1a. The N-oxy-2-pyridinyl moiety not only provided the structural motif required for agonist function but also reduced metabolism rates. The SAR study leading to the discovery of 6b is described herein.
ESTHER : Patel_2006_J.Med.Chem_49_7450
PubMedSearch : Patel_2006_J.Med.Chem_49_7450
PubMedID: 17149874