Hakeem AA

References (3)

Title : 1-aryl-3-(4-pyridine-2-ylpiperazin-1-yl)propan-1-one oximes as potent dopamine D4 receptor agonists for the treatment of erectile dysfunction - Kolasa_2006_J.Med.Chem_49_5093
Author(s) : Kolasa T , Matulenko MA , Hakeem AA , Patel MV , Mortell K , Bhatia P , Henry R , Nakane M , Hsieh GC , Terranova MA , Uchic ME , Miller LN , Chang R , Donnelly-Roberts D , Namovic MT , Hollingsworth PR , Martino B , El Kouhen O , Marsh KC , Wetter JM , Moreland RB , Brioni JD , Stewart AO
Ref : Journal of Medicinal Chemistry , 49 :5093 , 2006
Abstract : A new series of dopamine D4 receptor agonists, 1-aryl-3-(4-pyridinepiperazin-1-yl)propanone oximes, was designed through the modification of known dopamine D4 receptor agonist PD 168077. Replacement of the amide group with a methylene-oxime moiety produced compounds with improved stability and efficacy. Structure-activity relationsips (SAR) of the aromatic ring linked to the N-4-piperazine ring confirmed the superiority of 2-pyridine as a core for D4 agonist activity. A two-methylene linker between the oxime group and the N-1-piperazine ring displayed the best profile. New dopamine D4 receptor agonists, exemplified by (E)-1-(4-chlorophenyl)-3-(4-pyridin-2-ylpiperazin-1-yl)propan-1-one O-methyloxime (59a) and (E)-1-(3-chloro-4-fluorophenyl)-3-(4-pyridin-2-ylpiperazin-1-yl)propan-1-one O-methyloxime (64a), exhibited favorable pharmacokinetic profiles and showed oral bioavailability in rat and dog. Subsequent evaluation of 59a in the rat penile erection model revealed in vivo activity, comparable in efficacy to apomorphine. Our results suggest that the oximes provide a novel structural linker for 4-arylpiperazine-based D4 agonists, possessing leadlike quality and with potential to develop a new class of potent and selective dopamine D4 receptor agonists.
ESTHER : Kolasa_2006_J.Med.Chem_49_5093
PubMedSearch : Kolasa_2006_J.Med.Chem_49_5093
PubMedID: 16913699

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

Title : Synthesis and functional activity of (2-aryl-1-piperazinyl)-N-(3-methylphenyl)acetamides: selective dopamine D4 receptor agonists - Matulenko_2004_Bioorg.Med.Chem_12_3471
Author(s) : Matulenko MA , Hakeem AA , Kolasa T , Nakane M , Terranova MA , Uchic ME , Miller LN , Chang R , Donnelly-Roberts D , Namovic MT , Moreland RB , Brioni JD , Stewart AO
Ref : Bioorganic & Medicinal Chemistry , 12 :3471 , 2004
Abstract : Diaryl piperazine acetamides were identified as potent and selective dopamine D(4) receptor agonists. Our strategy is based on an amide bond reversal of an acid sensitive, dopamine D(4) receptor partial agonist, PD 168077. This reversal provided compounds with excellent potency and improved stability. Systematic evaluation of the substitution on the aryl piperazine portion revealed a significant effect on functional activity. The synthesis and biological activity of these new dopamine D(4) agonists is discussed.
ESTHER : Matulenko_2004_Bioorg.Med.Chem_12_3471
PubMedSearch : Matulenko_2004_Bioorg.Med.Chem_12_3471
PubMedID: 15186832