907572-24-1Relevant articles and documents
Development of the Convergent, Kilogram-Scale Synthesis of an Antibacterial Clinical Candidate Using Enantioselective Hydrogenation
Benson, Helen,Bones, Karen,Churchill, Gwydion,Ford, Gair,Frodsham, Lianne,Janbon, Sophie,Millington, Fiona,Powell, Lyn,Raw, Steven A.,Reid, Julie,Stark, Andrew,Steven, Alan
, p. 588 - 598 (2020/05/19)
Early chemical development studies into the best way of assembling AZD9742, an antibacterial drug candidate, have involved swapping the order of two reductive aminations. The orthogonally functionalized aminopiperidine partner for these couplings is now enantioselectively synthesized using ruthenium-catalyzed asymmetric hydrogenation. The challenge of controlling defluorination through an appropriate catalyst choice has hitherto prevented this revised sequence from reaching its full potential. However, it is still shown to allow access to the active pharmaceutical ingredient in a stereochemically pure form and has been demonstrated on a multikilogram scale. The reductive aminations in both the original and revised sequences provided different scale-up challenges, and the solutions implemented are described.
Synthesis and evaluation of novel 1H-pyrrolo[2,3-b]pyridine-5-carboxamide derivatives as potent and orally efficacious immunomodulators targeting JAK3
Nakajima, Yutaka,Inoue, Takayuki,Nakai, Kazuo,Mukoyoshi, Koichiro,Hamaguchi, Hisao,Hatanaka, Keiko,Sasaki, Hiroshi,Tanaka, Akira,Takahashi, Fumie,Kunikawa, Shigeki,Usuda, Hiroyuki,Moritomo, Ayako,Higashi, Yasuyuki,Inami, Masamichi,Shirakami, Shohei
, p. 4871 - 4883 (2015/08/03)
Janus kinases (JAKs) regulate various inflammatory and immune responses and are targets for the treatment of inflammatory and immune diseases. As a novel class of immunomodulators targeting JAK3, 1H-pyrrolo[2,3-b]pyridine-5-carboxamide derivatives are promising candidates for treating such diseases. In chemical modification of lead compound 2, the substitution of a cycloalkyl ring for an N-cyanopyridylpiperidine in C4-position was effective for increasing JAK3 inhibitory activity. In addition, modulation of physical properties such as molecular lipophilicity and basicity was important for reducing human ether-a-go-go-related gene (hERG) inhibitory activity. Our optimization study gave compound 31, which exhibited potent JAK3 inhibitory activity as well as weak hERG inhibitory activity. In cellular assay, 31 exhibited potent immunomodulating effect on IL-2-stimulated T cell proliferation. In a pharmacokinetic study, good metabolic stability and oral bioavailability of 31 were achieved in rats, dogs, and monkeys. Further, 31 prolonged graft survival in an in vivo rat heterotopic cardiac transplant model.
Pyrrolamide DNA gyrase inhibitors: Optimization of antibacterial activity and efficacy
Sherer, Brian A.,Hull, Kenneth,Green, Oluyinka,Basarab, Gregory,Hauck, Sheila,Hill, Pamela,Loch III, James T.,Mullen, George,Bist, Shanta,Bryant, Joanna,Boriack-Sjodin, Ann,Read, Jon,Degrace, Nancy,Uria-Nickelsen, Maria,Illingworth, Ruth N.,Eakin, Ann E.
scheme or table, p. 7416 - 7420 (2012/02/04)
The pyrrolamides are a new class of antibacterial agents targeting DNA gyrase, an essential enzyme across bacterial species and inhibition results in the disruption of DNA synthesis and subsequently, cell death. The optimization of biochemical activity an
