The blockade of the HIV protease has become a major target in the search for an effective therapy for AIDS.
While many reports of potent HIV-1 inhibitors have appeared recently, the compound Ro ...31-8959 remains the least selective for the HIV-1 and HIV-2 proteases.
This property may result in reduced susceptibility to resistance since these represent the genetically most divergent strains of HIV presently known to exist.
Cyclic sulfone-3-carboxamides are effective P
2-ligands for HIV-1 protease inhibitors. Incorporation of 3S-tetrahydro-2H-thiopyrancarboxamide-1,1-dioxide in the hydroxyethylamine series resulted in ...inhibitor 14 (IC
50=9 nM, CIC
95=200 nM) with improved potency compared to its corresponding urethane derivative 18 (IC
50=2.0 μM).
Incorporation of 3S-tetrahydro-2H-thiopyrancarboxamide-1,1-dioxide as P
2-ligand in the hydroxyethylamine series resulted in a HIV-1 protease inhibitor with improved potency compared to its corresponding urethane derivative.
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IJS, IMTLJ, KILJ, KISLJ, NUK, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Modification of the potent fibrinogen receptor (αIIbβ3) antagonist 1 generated compounds with high affinity for the vitronectin receptor αvβ3. Sequential modification of the basic N-terminus of 1 led ...to the identification of the 5,6,7,8-tetrahydro1,8naphthyridine moiety (THN) as a lipophilic, moderately basic N-terminus that provides molecules with excellent potency and selectivity for the integrin receptor αvβ3. The THN-containing analogue 5 is a potent inhibitor of bone resorption in vitro and in vivo. In addition, the identification of a novel, nonpeptide radioligand with high affinity to αvβ3 is also reported.
Mimetics of the RGD tripeptide are described that are potent, selective antagonists of the integrin receptor, alpha(v)beta(3). The use of the 5,6,7,8-tetrahydro1,8naphthyridine group as a ...potency-enhancing N-terminus is demonstrated. Two 3-substituted-3-amino-propionic acids previously contained in alpha(IIb)beta(3) antagonists were utilized to enhance binding affinity and functional activity for the targeted receptor. Further affinity increases were then achieved through the use of cyclic glycyl amide bond constraints.
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IJS, IMTLJ, KILJ, KISLJ, NUK, SBCE, SBJE, UL, UM, UPCLJ, UPUK
By tethering of a polar hydrophilic group to the P1 or P1' substituent of a Phe-based hydroxyethylene isostere, the antiviral potency of a series of HIV protease inhibitors was improved. The optimum ...enhancement of anti-HIV activity was observed with the 4-morpholinylethoxy substituent. The substituent effect is consistent with a model derived from inhibitor docked in the crystal structure of the native enzyme. An X-ray crystal structure of the inhibited enzyme determined to 2.25 A verifies the modeling predictions.
The replacement of the peptide bond with a functionality that mimics the biological mode of action continues to be a major strategy for drug design. As part of our continuing efforts in search of ...therapeutic agents for AIDS, we recently described a stereochemically defined tetrahydrofuran ring as a surrogate for the asparagine side chain in the design of HIV protease inhibitors. We were intrigued by the possibility of further exploiting this concept with the ultimate goal of producing a polyether template to mimic the peptide region which binds to the viral enzyme. After visual inspection of the X-ray crystal structure of the HIV-1 protease-inhibitor (Ro 31-8959) complex, it was tempting to speculate that a fused bicyclic tetrahydrofuran could effectively hydrogen bond to the NH of the Asp 29 and 30 residues and thereby replace the quinaldic amide-asparagine amide fragment of the Ro 31-8959 inhibitor. In the hydroxyethylamine isostere derived inhibitors of which Ro 31-8959 is prototypical, inclusion of a P sub(3) ligand is essential for low nanomolar activity against the HIV protease. Since there was considerable rotational freedom about the four bonds connecting the two carbonyls involved, a rigid cyclically constrained system might provide additional gains in binding energy, to offset loss of the P sub(3) hydrophobic binding of the quinoline ring. In this paper, we report the structure-based design of a fused bis-tetrahydrofuran that effectively replaces two amide bonds and a 10 pi -aromatic system of the present clinical candidate (Ro 31-8959).
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