Piperazine-based CCR5 antagonists as HIV-1 inhibitors. III: Synthesis, antiviral and Pharmacokinetic profiles of symmetrical Heteroaryl Carboxamides

被引:55
作者
McCombie, SW [1 ]
Tagat, JR [1 ]
Vice, SF [1 ]
Lin, SI [1 ]
Steensma, R [1 ]
Palani, A [1 ]
Neustadt, BR [1 ]
Baroudy, BM [1 ]
Strizki, JM [1 ]
Endres, M [1 ]
Cox, K [1 ]
Dan, N [1 ]
Chou, CC [1 ]
机构
[1] Schering Plough Corp, Res Inst, Kenilworth, NJ 07033 USA
关键词
D O I
10.1016/S0960-894X(02)00918-6
中图分类号
R914 [药物化学];
学科分类号
100701 ;
摘要
The unsymmetrical nicotinamide-N-oxide moiety in compound I was replaced with symmetrical isonicotinamides as well as 4,6-dimethyl pyrimidine-5-carboxamides. Compound 16 from the latter set reduced the number of rotamers, improved potency of inhibiting UIV entry, slightly diminished the affinity for the muscarine receptors and showed very good oral absorption. (C) 2002 Elsevier Science Ltd. All rights reserved.
引用
收藏
页码:567 / 571
页数:5
相关论文
共 19 条
[11]   CCR5 antagonists:: Bicyclic isoxazolidines as conformationally constrained N-1-substituted pyrrolidines [J].
Lynch, CL ;
Gentry, AL ;
Hale, JJ ;
Mills, SG ;
MacCoss, M ;
Malkowitz, L ;
Springer, MS ;
Gould, SL ;
DeMartino, JA ;
Siciliano, SJ ;
Cascieri, MA ;
Doss, G ;
Carella, A ;
Carver, G ;
Holmes, K ;
Schleif, WA ;
Danzeisen, R ;
Hazuda, D ;
Kessler, J ;
Lineberger, J ;
Miller, M ;
Emini, EA .
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, 2002, 12 (04) :677-679
[12]   Novel low molecular weight spirodiketopiperazine derivatives potently inhibit R5 HIV-1 infection through their antagonistic effects on CCR5 [J].
Maeda, K ;
Yoshimura, K ;
Shibayama, S ;
Habashita, H ;
Tada, H ;
Sagawa, K ;
Miyakawa, T ;
Aoki, M ;
Fukushima, D ;
Mitsuya, H .
JOURNAL OF BIOLOGICAL CHEMISTRY, 2001, 276 (37) :35194-35200
[13]  
MCCOMBIE S, 2002, 223 ACS NAT M ORL FL
[14]  
OKAMOTO T, 1966, CHEM PHARM BULL, V14, P518
[15]   Discovery of 4-[(Z)-(4-bromophenyl)-(ethoxyimino)methyll-1′-[(2,4-dimethyl-3-pyridinyl)carbonyl]-4′-methyl-1,4′-bipiperidine N-oxide (SCH 351125):: An orally bioavailable human CCR5 antagonist for the treatment of HIV infection [J].
Palani, A ;
Shapiro, S ;
Clader, JW ;
Greenlee, WJ ;
Cox, K ;
Strizki, J ;
Endres, M ;
Baroudy, BM .
JOURNAL OF MEDICINAL CHEMISTRY, 2001, 44 (21) :3339-3342
[16]   Discovery of novel, potent, and selective small-molecule CCR5 antagonists as anti-HIV-1 agents: Synthesis and biological evaluation of anilide derivatives with a quaternary ammonium moiety [J].
Shiraishi, M ;
Aramaki, Y ;
Seto, M ;
Imoto, H ;
Nishikawa, Y ;
Kanzaki, N ;
Okamoto, M ;
Sawada, H ;
Nishimura, O ;
Baba, M ;
Fujino, M .
JOURNAL OF MEDICINAL CHEMISTRY, 2000, 43 (10) :2049-2063
[17]   SCH-C (SCH 351125), an orally bioavailable, small molecule antagonist of the chemokine receptor CCR5, is a potent inhibitor of HIV-1 infection in vitro and in vivo [J].
Strizki, JM ;
Xu, S ;
Wagner, NE ;
Wojcik, L ;
Liu, J ;
Hou, Y ;
Endres, M ;
Palani, A ;
Shapiro, S ;
Clader, JW ;
Greenlee, WJ ;
Tagat, JR ;
McCombie, S ;
Cox, K ;
Fawzi, AB ;
Chou, CC ;
Pugliese-Sivo, C ;
Davies, L ;
Moreno, ME ;
Ho, DD ;
Trkola, A ;
Stoddart, CA ;
Moore, JP ;
Reyes, GR ;
Baroudy, BM .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2001, 98 (22) :12718-12723
[18]   Piperazine-based CCR5 antagonists as HIV-1 inhibitors.: I:: 2(S)-methyl piperazine as a key pharmacophore element [J].
Tagat, JR ;
McCombie, SW ;
Steensma, RW ;
Lin, SI ;
Nazareno, DV ;
Baroudy, B ;
Vantuno, N ;
Xu, S ;
Liu, J .
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, 2001, 11 (16) :2143-2146
[19]   Piperazine-based CCR5 antagonists as HIV-1 inhibitors.: II.: Discovery of 1-[(2,4-dimethyl-3-pyridinyl)carbonyl]-4-methyl-4-[3(S)-methyl-4-[1(S)-[4-(trifluoro-methyl)phenyl]ethyl]-1-piperazinyl]-piperidine N1-oxide (Sch-350634), an orally bioavailable, potent CCR5 antagonist [J].
Tagat, JR ;
Steensma, RW ;
McCombie, SW ;
Nazareno, DV ;
Lin, SI ;
Neustadt, BR ;
Cox, K ;
Xu, S ;
Wojcik, L ;
Murray, MG ;
Vantuno, N ;
Baroudy, BM ;
Strizki, JM .
JOURNAL OF MEDICINAL CHEMISTRY, 2001, 44 (21) :3343-3346