The CCR5 receptor-based mechanism of action of 873140, a potent allosteric noncompetitive HIV entry inhibitor.
4-{[4-({(3R)-1-Butyl-3-[(R)-cyclohexyl(hydroxy)methyl]-2,5dioxo-1,4,9-triazaspiro[5.5]undec-9-yl}methyl)phenyl]oxy}benzoic acid hydrochloride (873140) is a potent noncompetitive allosteric antagonist of the CCR5 receptor (pK(B) = 8.6 +/- 0.07; 95% CI, 8.5 to 8.8) with concomitantly potent antiviral effects for HIV-1. In this article, the receptor-based mechanism of action of 873140 is compared with four other noncompetitive allosteric antagonists of CCR5. Although (Z)-(4-bromophenyl){1'-[(2,4-dimethyl-1-oxido-3-pyridinyl)carbonyl]-4'-methyl-1,4'-bipiperidin-4-yl}methanone O-ethyloxime (Sch-C; SCH 351125), 4,6-dimethyl-5-{[4-methyl-4-((3S)-3-methyl-4-{(1R)-2-(methyloxy)-1-[4-(trifluoromethyl)phenyl]ethyl}-1-piperazinyl)-1-piperidinyl]carbonyl}pyrimidine (Sch-D; SCH 417,690), 4,4-difluoro-N-((1S)-3-{(3-endo)-3-[3-methyl-5-(1-methylethyl)-4H-1,2,4-triazol-4-yl]-8-azabicyclo[3.2.1]oct-8-yl}-1-phenyl-propyl)cyclohexanecarboxamide (UK-427,857), and N,N-dimethyl-N-[4-[[[2-(4-methylphenyl)-6,7-dihydro-5H-benzocyclo-hepten-8-yl]carbonyl]amino]benzyl]tetrahydro-2H-pyran-4-aminium chloride (TAK779) blocked the binding of both chemokines (125)I-MIP-1alpha (also known as (125)I-CCL3, (125)I-LD78) and (125)I-RANTES ((125)I-CCL5), 873140 was an ineffectual antagonist of (125)I-RANTES (regulated on activation normal T cell expressed and secreted) binding (but did block binding of (125)I-MIP-1alpha). Furthermore, 873140 blocked the calcium response effects of CCR5 activation by CCL5 (RANTES) (as did the other antagonists), indicating a unique divergence of blockade of function and binding with this antagonist. The antagonism of CCR5 by 873140 is saturable and probe-dependent, consistent with an allosteric mechanism of action. The blockade of CCR5 by 873140 was extremely persistent with a rate constant for reversal of <0.004 h(-) (1) (t(1/2) > 136 h). Coadministration studies of 873140 with the four other allosteric antagonists yielded data that are consistent with the notion that all five of these antagonists bind to a common allosteric site on the CCR5 receptor. Although these ligands may have a common binding site, they do not exert the same allosteric effect on the receptor, as indicated by their differential effects on the binding of (125)I-RANTES. This idea is discussed in terms of using these drugs sequentially to overcome HIV viral resistance in the clinic.
Watson
Christian
C
Assay Development and Compound Profiling, GlaxoSmithKline Research and Development, 5 Moore Drive, Research Triangle Park, NC 27709, USA.
Jenkinson
Stephen
S
Kazmierski
Wieslaw
W
Kenakin
Terry
T
D000818:Animals; D019380:Anti-HIV Agents / Q000494:pharmacology*; D001565:Benzoates / Q000494:pharmacology*; D065100:CCR5 Receptor Antagonists; D016466:CHO Cells; D054405:Chemokine CCL3; D054407:Chemokine CCL4; D018946:Chemokine CCL5 / Q000378:metabolism; D006224:Cricetinae; D003497:Cyclic N-Oxides / Q000494:pharmacology; D054659:Diketopiperazines; D004305:Dose-Response Relationship, Drug; D024882:Drug Resistance, Viral; D019402:Macrophage Inflammatory Proteins / Q000378:metabolism; D010091:Oximes; D010879:Piperazines; D010880:Piperidines / Q000494:pharmacology; D011725:Pyridines / Q000494:pharmacology; D013141:Spiro Compounds / Q000494:pharmacology*
D019380:Anti-HIV Agents; D001565:Benzoates; D065100:CCR5 Receptor Antagonists; D054405:Chemokine CCL3; D054407:Chemokine CCL4; D018946:Chemokine CCL5; D003497:Cyclic N-Oxides; D054659:Diketopiperazines; D019402:Macrophage Inflammatory Proteins; D010091:Oximes; D010879:Piperazines; D010880:Piperidines; D011725:Pyridines; D013141:Spiro Compounds; C438583:Ancriviroc; C499671:aplaviroc