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

Jayaram R Tagat; Stuart W McCombie; Dennis Nazareno; Marc A Labroli; Yushi Xiao; Ruo W Steensma; Julie M Strizki; Bahige M Baroudy; Kathleen Cox; Jean Lachowicz; Geoffrey Varty; Robert Watkins

doi:10.1021/jm0304515

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

J Med Chem. 2004 May 6;47(10):2405-8. doi: 10.1021/jm0304515.

Authors

Jayaram R Tagat¹, Stuart W McCombie, Dennis Nazareno, Marc A Labroli, Yushi Xiao, Ruo W Steensma, Julie M Strizki, Bahige M Baroudy, Kathleen Cox, Jean Lachowicz, Geoffrey Varty, Robert Watkins

Affiliation

¹ Schering-Plough Research Institute, K-15-2B-2800, 2015 Galloping Hill Road, Kenilworth, New Jersey 07033, USA. jayaram.tagat@spcorp.com

PMID: 15115380
DOI: 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.

MeSH terms

Administration, Oral
Animals
Anti-HIV Agents / adverse effects
Anti-HIV Agents / chemical synthesis*
Anti-HIV Agents / pharmacology
Biological Availability
Brain / drug effects
CCR5 Receptor Antagonists*
Cation Transport Proteins / drug effects
Digestive System / drug effects
Ether-A-Go-Go Potassium Channels
HIV-1 / drug effects*
HIV-1 / isolation & purification
Humans
In Vitro Techniques
Leukocytes, Mononuclear / drug effects
Leukocytes, Mononuclear / virology
Macaca fascicularis
Piperazines / adverse effects
Piperazines / chemical synthesis*
Piperazines / chemistry
Piperazines / pharmacology
Piperidines / chemical synthesis*
Piperidines / chemistry
Piperidines / pharmacology
Potassium Channels / drug effects
Potassium Channels, Voltage-Gated*
Pyrimidines / adverse effects
Pyrimidines / chemical synthesis*
Pyrimidines / chemistry
Pyrimidines / pharmacology
Rats
Stereoisomerism
Structure-Activity Relationship

Substances

Anti-HIV Agents
CCR5 Receptor Antagonists
Cation Transport Proteins
Ether-A-Go-Go Potassium Channels
KCNH6 protein, human
Piperazines
Piperidines
Potassium Channels
Potassium Channels, Voltage-Gated
Pyrimidines
vicriviroc