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.
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.
Tagat
Jayaram R
JR
Schering-Plough Research Institute, K-15-2B-2800, 2015 Galloping Hill Road, Kenilworth, New Jersey 07033, USA. jayaram.tagat@spcorp.com
McCombie
Stuart W
SW
Nazareno
Dennis
D
Labroli
Marc A
MA
Xiao
Yushi
Y
Steensma
Ruo W
RW
Strizki
Julie M
JM
Baroudy
Bahige M
BM
Cox
Kathleen
K
Lachowicz
Jean
J
Varty
Geoffrey
G
Watkins
Robert
R
D000284:Administration, Oral; D000818:Animals; D019380:Anti-HIV Agents / Q000009:adverse effects / Q000138:chemical synthesis* / Q000494:pharmacology; D001682:Biological Availability; D001921:Brain / Q000187:drug effects; D065100:CCR5 Receptor Antagonists; D027682:Cation Transport Proteins / Q000187:drug effects; D004064:Digestive System / Q000187:drug effects; D051638:Ether-A-Go-Go Potassium Channels; D015497:HIV-1 / Q000187:drug effects* / Q000302:isolation & purification; D006801:Humans; D066298:In Vitro Techniques; D007963:Leukocytes, Mononuclear / Q000187:drug effects / Q000821:virology; D008252:Macaca fascicularis; D010879:Piperazines / Q000009:adverse effects / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D010880:Piperidines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D015221:Potassium Channels / Q000187:drug effects; D024642:Potassium Channels, Voltage-Gated; D011743:Pyrimidines / Q000009:adverse effects / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D051381:Rats; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
D019380:Anti-HIV Agents; D065100:CCR5 Receptor Antagonists; D027682:Cation Transport Proteins; D051638:Ether-A-Go-Go Potassium Channels; C092509:KCNH6 protein, human; D010879:Piperazines; D010880:Piperidines; D015221:Potassium Channels; D024642:Potassium Channels, Voltage-Gated; D011743:Pyrimidines; C486781:vicriviroc