Piperazine-Based CCR5 Antagonists as HIV-1 Inhibitors. IV. Discovery of 1-[(4,6-Dimethyl-5-pyrimidinyl)carbonyl]- 4-[4-{2-methoxy-1(R)-4-(trifluoromethyl)phenyl}ethyl-3(S)-methyl-1-piperazinyl]- 4-methylpiperidine (Sch-417690/Sch-D), a Potent, Highly Selective, and Orally Bioavailable CCR5 Antagonist
- 9 April 2004
- journal article
- letter
- Published by American Chemical Society (ACS) in Journal of Medicinal Chemistry
- Vol. 47 (10) , 2405-2408
- https://doi.org/10.1021/jm0304515
Abstract
The nature and the size of the benzylic substituent are shown to be the key to controlling receptor selectivity (CCR5 vs M1, M2) and potency in the title compounds. Optimization of the lead benzylic methyl compound 3 led to the methoxymethyl analogue 30, which had excellent receptor selectivity and oral bioavailability in rats and monkeys. Compound 30 (Sch-417690/Sch-D), a potent inhibitor of HIV-1 entry into target cells, is currently in clinical trials.Keywords
This publication has 11 references indexed in Scilit:
- The impact of drug-induced QT interval prolongation on drug discovery and developmentNature Reviews Drug Discovery, 2003
- Understanding the Structure−Activity Relationship of the Human Ether-a-go-go-Related Gene Cardiac K+ Channel. A Model for Bad BehaviorJournal of Medicinal Chemistry, 2003
- Piperazine-based CCR5 antagonists as HIV-1 inhibitors. III: synthesis, antiviral and pharmacokinetic profiles of symmetrical heteroaryl carboxamidesBioorganic & Medicinal Chemistry Letters, 2003
- 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 AntagonistJournal of Medicinal Chemistry, 2001
- Discovery of 4-[(Z)-(4-Bromophenyl)- (ethoxyimino)methyl]-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 InfectionJournal of Medicinal Chemistry, 2001
- Primary HIV-1 ResistanceJAMA, 1999
- CHEMOKINE RECEPTORS AS HIV-1 CORECEPTORS: Roles in Viral Entry, Tropism, and DiseaseAnnual Review of Immunology, 1999
- On the reduction of α-aminonitriles with sodiumTetrahedron Letters, 1989
- Isolation and characterization of a stable simple enolJournal of the American Chemical Society, 1987
- N-methoxy-n-methylamides as effective acylating agentsTetrahedron Letters, 1981