Piperazine-based CCR5 antagonists as HIV-1 inhibitors. III: synthesis, antiviral and pharmacokinetic profiles of symmetrical heteroaryl carboxamides.
The unsymmetrical nicotinamide-N-oxide moiety in compound 1 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.
McCombie
Stuart W
SW
Schering-Plough Research Institute, 2015 Galloping Hill Road, K-15-2B-2800, Kenilworth, NJ 07033, USA.
Tagat
Jayaram R
JR
Vice
Susan F
SF
Lin
Sue-Ing
SI
Steensma
Ruo
R
Palani
Anandan
A
Neustadt
Bernard R
BR
Baroudy
Bahige M
BM
Strizki
Julie M
JM
Endres
Michael
M
Cox
Kathleen
K
Dan
Niya
N
Chou
Chuan-Chu
CC
D000284:Administration, Oral; D000818:Animals; D019380:Anti-HIV Agents / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology*; D019540:Area Under Curve; D065100:CCR5 Receptor Antagonists; D055598:Chemical Phenomena; D002627:Chemistry, Physical; D015497:HIV-1 / Q000187:drug effects*; D006207:Half-Life; D006571:Heterocyclic Compounds / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000494:pharmacology; D006801:Humans; D007275:Injections, Intravenous; D007408:Intestinal Absorption; D008968:Molecular Conformation; D010879:Piperazines / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology*; D051381:Rats; D011976:Receptors, Muscarinic / Q000187:drug effects; D013329:Structure-Activity Relationship
D019380:Anti-HIV Agents; D065100:CCR5 Receptor Antagonists; D006571:Heterocyclic Compounds; D010879:Piperazines; D011976:Receptors, Muscarinic