122334-02-5Relevant articles and documents
Stereoselective Synthesis of the Spirocyclic γ-Lactam Core of the Ansalactams
Liang, Zhanhao,Lin, You-Chen,Pierce, Joshua G.
supporting information, p. 9559 - 9562 (2021/12/14)
Ansalactam A is an ansa macrolide natural product that contains a densely functionalized spiro-γ-lactam core containing three contiguous stereocenters. This unusual motif distinguishes it from other members of this family and represents a significant synthetic challenge. Herein, we report the development of a stereoselective formal [3+2] cycloaddition reaction for the construction of this key spiro-γ-lactam motif for the first time, thereby enabling access to the northern domain of ansalactam A.
Discovery of a 1-Methyl-3,4-dihydronaphthalene-Based Sphingosine-1-Phosphate (S1P) Receptor Agonist Ceralifimod (ONO-4641). A S1P1 and S1P5 Selective Agonist for the Treatment of Autoimmune Diseases
Kurata, Haruto,Kusumi, Kensuke,Otsuki, Kazuhiro,Suzuki, Ryo,Kurono, Masakuni,Komiya, Takaki,Hagiya, Hiroshi,Mizuno, Hirotaka,Shioya, Hiroki,Ono, Takeji,Takada, Yuka,Maeda, Tatsuo,Matsunaga, Norikazu,Kondo, Tetsu,Tominaga, Sachiko,Nunoya, Ken-Ici,Kiyoshi, Hidekazu,Komeno, Masaharu,Nakade, Shinji,Habashita, Hiromu
, p. 9508 - 9530 (2017/12/26)
The discovery of 1-({6-[(2-methoxy-4-propylbenzyl)oxy]-1-methyl-3,4-dihydronaphthalen-2-yl}methyl)azetidine-3-carboxylic acid 13n (ceralifimod, ONO-4641), a sphingosine-1-phosphate (S1P) receptor agonist selective for S1P1 and S1P5, is described. While it has been revealed that the modulation of the S1P1 receptor is an effective way to treat autoimmune diseases such as relapsing-remitting multiple sclerosis (RRMS), it was also reported that activation of the S1P3 receptor is implicated in some undesirable effects. We carried out a structure-activity relationship (SAR) study of hit compound 6 with an amino acid moiety in the hydrophilic head region. Following identification of a lead compound with a dihydronaphthalene central core by inducing conformational constraint, optimization of the lipophilic tail region led to the discovery of 13n as a clinical candidate that exhibited >30 000-fold selectivity for S1P1 over S1P3 and was potent in a peripheral lymphocyte lowering (PLL) test in mice (ED50 = 0.029 mg/kg, 24 h after oral dosing).
Bicyclic inhibitors of protein farnesyl transferase
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, (2008/06/13)
PCT No. PCT/US98/03025 Sec. 371 Date Aug. 2, 1999 Sec. 102(e) Date Aug. 2, 1999 PCT Filed Feb. 11, 1998 PCT Pub. No. WO98/34921 PCT Pub. Date Aug. 13, 1998The present invention provides compounds of Formula (I). The present invention also provides a metho
Introduction of a putative dopaminergic prodrug moiety into a 6,7-substitution pattern characteristic of certain 2-aminotetralin dopaminergic agonists
Cannon,True,Long,Bhatnagar,Leonard,Flynn
, p. 2210 - 2214 (2007/10/02)
On the basis of the premise that the dopaminergic agonist profile of 2-(di-n-propylamino)-5-hydroxy-6-methyltetralin (1a) is due to in vivo oxidation of the 6-methyl moiety and that 1a may represent a novel prodrug strategy, the vicinal methyl-hydroxyl substitution pattern was incorporated into the 6- and 7-positions of 2-(di-n-propylamino)tetralin to give the 6-methyl-7-hydroxy and 6-hydroxy-7-methyl isomers 8 and 9, respectively. A multistep synthetic approach was devised which permitted preparation of target molecules 8 and 9. Pharmacological data revealed that both target compounds exhibit modest dopamine-like effects in the cardioaccelerator nerve assay in the cat, but neither appeared to be metabolically activated as was the case with 1a. The effects of 9 (but not of 8) were antagonized by pretreatment with haloperidol. Thus, the 5-hydroxy-6-methyl substition pattern in the 2-aminotetralins remains unique as a dopaminergic agonist prodrug structure.
