41413-37-0Relevant articles and documents
Discovery of APD371: Identification of a Highly Potent and Selective CB2 Agonist for the Treatment of Chronic Pain
Han, Sangdon,Thoresen, Lars,Jung, Jae-Kyu,Zhu, Xiuwen,Thatte, Jayant,Solomon, Michelle,Gaidarov, Ibragim,Unett, David J.,Yoon, Woo Hyun,Barden, Jeremy,Sadeque, Abu,Usmani, Amin,Chen, Chuan,Semple, Graeme,Grottick, Andrew J.,Al-Shamma, Hussein,Christopher, Ronald,Jones, Robert M.
supporting information, p. 1309 - 1313 (2017/12/26)
The discovery of a novel, selective and fully efficacious CB2 agonist with satisfactory pharmacokinetic and pharmaceutical properties is described. Compound 6 was efficacious in a rat model of osteoarthritis pain following oral administration and, in contrast to morphine, maintained its analgesic effect throughout a 5-day subchronic treatment paradigm. These data were consistent with our hypothesis that full agonist efficacy is required for efficient internalization and recycling of the CB2 receptor to avoid tachyphylaxis. Based on its overall favorable preclinical profile, 6 (APD371) was selected for further development for the treatment of pain.
Discovery of 2-Pyridinone Aminals: A Prodrug Strategy to Advance a Second Generation of HIV-1 Integrase Strand Transfer Inhibitors
Raheem, Izzat T.,Walji, Abbas M.,Klein, Daniel,Sanders, John M.,Powell, David A.,Abeywickrema, Pravien,Barbe, Guillaume,Bennet, Amrith,Clas, Sophie-Dorothee,Dubost, David,Embrey, Mark,Grobler, Jay,Hafey, Michael J.,Hartingh, Timothy J.,Hazuda, Daria J.,Miller, Michael D.,Moore, Keith P.,Pajkovic, Natasa,Patel, Sangita,Rada, Vanessa,Rearden, Paul,Schreier, John D.,Sisko, John,Steele, Thomas G.,Truchon, Jean-Fran?ois,Wai, John,Xu, Min,Coleman, Paul J.
supporting information, p. 8154 - 8165 (2015/11/09)
The search for new molecular constructs that resemble the critical two-metal binding pharmacophore required for HIV integrase strand transfer inhibition represents a vibrant area of research within drug discovery. Here we present the discovery of a new class of HIV integrase strand transfer inhibitors based on the 2-pyridinone core of MK-0536. These efforts led to the identification of two lead compounds with excellent antiviral activity and preclinical pharmacokinetic profiles to support a once-daily human dose prediction. Dose escalating PK studies in dog revealed significant issues with limited oral absorption and required an innovative prodrug strategy to enhance the high-dose plasma exposures of the parent molecules.
Parallel and competitive pathways for substrate desaturation, hydroxylation, and radical rearrangement by the non-heme diiron hydroxylase AlkB
Cooper, Harriet L. R.,Mishra, Girish,Huang, Xiongyi,Pender-Cudlip, Marilla,Austin, Rachel N.,Shanklin, John,Groves, John T.
supporting information, p. 20365 - 20375 (2013/02/25)
A purified and highly active form of the non-heme diiron hydroxylase AlkB was investigated using the diagnostic probe substrate norcarane. The reaction afforded C2 (26%) and C3 (43%) hydroxylation and desaturation products (31%). Initial C-H cleavage at C2 led to 7% C2 hydroxylation and 19% 3-hydroxymethylcyclohexene, a rearrangement product characteristic of a radical rearrangement pathway. A deuterated substrate analogue, 3,3,4,4-norcarane-d 4, afforded drastically reduced amounts of C3 alcohol (8%) and desaturation products (5%), while the radical rearranged alcohol was now the major product (65%). This change in product ratios indicates a large kinetic hydrogen isotope effect of ～20 for both the C-H hydroxylation at C3 and the desaturation pathway, with all of the desaturation originating via hydrogen abstraction at C3 and not C2. The data indicate that AlkB reacts with norcarane via initial C-H hydrogen abstraction from C2 or C3 and that the three pathways, C3 hydroxylation, C3 desaturation, and C2 hydroxylation/radical rearrangement, are parallel and competitive. Thus, the incipient radical at C3 either reacts with the iron-oxo center to form an alcohol or proceeds along the desaturation pathway via a second H-abstraction to afford both 2-norcarene and 3-norcarene. Subsequent reactions of these norcarenes lead to detectable amounts of hydroxylation products and toluene. By contrast, the 2-norcaranyl radical intermediate leads to C2 hydroxylation and the diagnostic radical rearrangement, but this radical apparently does not afford desaturation products. The results indicate that C-H hydroxylation and desaturation follow analogous stepwise reaction channels via carbon radicals that diverge at the product-forming step.
