55314-29-9Relevant articles and documents
Discovery and preclinical characterization of 1-methyl-3-(4-methylpyridin- 3-yl)-6-(pyridin-2-ylmethoxy)-1H-pyrazolo-[3,4-b]pyrazine (PF470): A highly potent, selective, and efficacious metabotropic glutamate receptor 5 (mGluR5) negative allosteric modulator
Zhang, Lei,Balan, Gayatri,Barreiro, Gabriela,Boscoe, Brian P.,Chenard, Lois K.,Cianfrogna, Julie,Claffey, Michelle M.,Chen, Laigao,Coffman, Karen J.,Drozda, Susan E.,Dunetz, Joshua R.,Fonseca, Kari R.,Galatsis, Paul,Grimwood, Sarah,Lazzaro, John T.,Mancuso, Jessica Y.,Miller, Emily L.,Reese, Matthew R.,Rogers, Bruce N.,Sakurada, Isao,Skaddan, Marc,Smith, Deborah L.,Stepan, Antonia F.,Trapa, Patrick,Tuttle, Jamison B.,Verhoest, Patrick R.,Walker, Daniel P.,Wright, Ann S.,Zaleska, Margaret M.,Zasadny, Kenneth,Shaffer, Christopher L.
, p. 861 - 877 (2014)
A novel series of pyrazolopyrazines is herein disclosed as mGluR5 negative allosteric modulators (NAMs). Starting from a high-throughput screen (HTS) hit (1), a systematic structure-activity relationship (SAR) study was conducted with a specific focus on balancing pharmacological potency with physicochemical and pharmacokinetic (PK) properties. This effort led to the discovery of 1-methyl-3-(4-methylpyridin-3-yl)-6-(pyridin-2-ylmethoxy)-1H-pyrazolo[3,4-b] pyrazine (PF470, 14) as a highly potent, selective, and orally bioavailable mGluR5 NAM. Compound 14 demonstrated robust efficacy in a 1-methyl-4-phenyl-1,2, 3,6-tetrahydropyridine (MPTP)-rendered Parkinsonian nonhuman primate model of l-DOPA-induced dyskinesia (PD-LID). However, the progression of 14 to the clinic was terminated because of a potentially mechanism-mediated finding consistent with a delayed-type immune-mediated type IV hypersensitivity in a 90-day NHP regulatory toxicology study.
Synthesis of regioisomeric pyrido[c]azocanones from azaindanone derivatives
Penning, Miriam,Christoffers, Jens
, p. 2140 - 2149 (2014/04/17)
A ring enlargement reaction with methylamine gave new pyrido[2,3-c]-, pyrido[3,4-c]- and pyrido[3,2-c]azocanone derivatives from cyclic β-oxo esters with a cyclopentapyridine skeleton and a 1,4-diketone moiety. The starting materials for this ring transformation were either prepared from halogenopyridine carboxylates by Heck reaction and subsequent hydrogenation, or (halogenomethyl)pyridine carboxylates were submitted to SN reaction with diethyl malonate. Both routes were completed by Dieckmann condensation to build the cyclic β-oxo ester structure and alkylation with phenacylbromide to install the 1,4-diketone motif. Copyright
Evaluation of the first cytostatically active 1-aza-9-oxafluorenes as novel selective CDK1 inhibitors with P-glycoprotein modulating properties
Brachwitz, Kristin,Voigt, Burkhardt,Meijer, Laurent,Lozach, Olivier,Sch?chtele, Christoph,Molnár, Josef,Hilgeroth, Andreas
, p. 876 - 879 (2007/10/03)
The first series of synthetic 1-aza-9-oxafluorenes with cytostatic activities in the micromolar range was evaluated as cyclin-dependent kinase (CDK1) inhibitors. Activity was found to be selective in comparison to the inhibition of other kinases within th
