Highly Potent and Orally Active CCR5 Antagonists as Anti-HIV-1 Agents:  Synthesis and Biological Activities of 1-Benzazocine Derivatives Containing a Sulfoxide Moiety

Abstract

Chemical modification has been performed on an orally bioavailable and potent CCR5 antagonist, sulfoxide compound 4, mainly focusing on replacement of the [6,7]-fused 1-benzazepine nucleus. We designed, synthesized, and evaluated the biological activities of ring-expanded [6,8]-, [6,9]-, and [6,10]-fused compounds containing S-sulfoxide moieties, which led to the discovery of 1-benzazocine and 1-benzazonine compounds that exhibited potent inhibitory activities (equivalent to compound 4) in a binding assay. In addition, 1-benzazocine compounds possessing the S-sulfoxide moiety ((S)-(-)-5a,b,d,e) showed greater potency than compound 4 in a fusion assay. From further investigation in a multi-round infection assay, it was found that 1-isobutyl-1-benzazocine compound (S)-(-)-5b, containing the S-{[(1-propyl-1H-imidazol)-5-yl]methyl}sulfinyl group, showed the most potent anti-HIV-1 activity (IC90=0.81 nM, in MOLT4/CCR5 cells). Compound (S)-(-)-5b (TAK-652) also inhibited the replication of six macrophage-tropic (CCR5-using or R5) HIV-1 clinical isolates in peripheral blood mononuclear cells (PBMCs) (mean IC90=0.25 nM). It was also absorbed after oral administration in rats, dogs, and monkeys and was thus selected as a clinical candidate. The synthesis and biological activity of the 1-benzazocine compound (S)-(-)-5b and its related derivatives are described.

The Lupane-type Triterpene 30-Oxo-calenduladiol Is a CCR5 Antagonist with Anti-HIV-1 and Anti-chemotactic Activities

“…This region represents the conformational binding domain for the neutralizing antibody 2D7 (27), which has been involved in ligand/ or virus/receptor interaction (27)(28)(29)(30). However, as occurs with other antiviral small molecules (31)(32)(33)(34), it is also plausible that compound 1 may occupy the CCR5 pocket, inducing a conformational change that may affect the second extracellular loop of CCR5, impairing its recognition by the anti-CCR5 mAb CD195 (2D7). These potential conformational changes may also affect RANTES-CCR5 binding and CCR5/ gp120-mediated R5-tropic HIV-1 viral infection.…”

Molecular Interactions of CCR5 with Major Classes of Small-Molecule Anti-HIV CCR5 Antagonists

“…For CCR5 antagonists SCH-C (Palani et al, 2002), VVC (SCH-D; Strizki et al, 2005), maraviroc (MVC; Wood and Armour, 2005), aplaviroc (APL; Watson et al, 2005), TAK-779 (Baba et al, 1999), and TAK-220 (Imamura et al, 2006;Seto et al, 2006) please refer to their respective publications.…”

“…This compound was terminated as a result of poor oral availability. Two structurally diverse followers TAK-220 and TAK-652 are both in clinical trials (Imamura et al, 2006;Seto et al, 2006). Several other small molecule CCR5 antagonists with good potency and/or pharmacological properties have also been reported by other pharmaceutical companies.…”

Synthesis of Benzoazocines from Substituted Tetrahydroisoquinolines and Activated Alkynes in a Tetrahydropyridine Ring Expansion

“…Alkaloids and drugs containing benzoazocine fragments in their structures exhibit extensive evidence of different activities: inhibition of α-glucosidase, [2] acetylcholinesterase, [3] antinociception activity, [4] antitumor activity, [5] antiinsectan activity, [6] and inhibition of HIV-1 replication. [7] Known synthetic routes towards the benzoazocine system include ring-closing metathesis, [8] intramolecular catalytic Friedel-Crafts reactions, [9] and palladium-catalyzed heteroannulation, [10] but only a few of these are really effective. [11] Recently, we have reported a novel method for the synthesis of tetrahydropyrrolo [2,3-d]azocines, [12] tetrahydroazocino [4,5-b]-and - [5,4-b]indoles, [13] and hexahydroazonino [5,6-b]indoles.…”