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We present several novel P1/P1' substituents that can replace the characteristic benzyl P1/P1' moiety of the cyclic urea based HIV protease inhibitor series. These substituents typically provide 5-10-fold improvements in binding affinity compared to the unsubstituted benzyl analogs. The best substituent was the 3,4-(ethylenedioxy)benzyl group. Proper balancing of the molecule's lipophilicity facilitated the transfer of this improved binding affinity into a superior cellular antiviral activity profile. Several analogs were evaluated further for protein binding and resistance liabilities. Compound 18 (IC90 = 8.7 nM) was chosen for oral bioavailability studies based on its log P and solubility profile. A 10 mg/kg dose in dogs provided modest bioavailability with Cmax = 0.22 microg/mL. X-ray crystallographic analysis of two analogs revealed several interesting features responsible for the 3,4-(ethylenedioxy)benzyl-substituted analog's potency: (1) Comparing the two complexes revealed two distinct binding modes for each P1/P1' substituent; (2) The ethylenedioxy moieties are within 3.6 A of Pro 81 providing additional van der Waals contacts missing from the parent structure; (3) The enzyme's Arg 8 side chain moves away from the P1 substituent to accommodate the increased steric volume while maintaining a favorable hydrogen bond distance between the para oxygen substituent and the guanidine NH.

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Carbohydrates Carbohydrates U 0500 Synthesis of Novel HIV-1 Protease Inhibitors Based on Carbohydrate Scaffolds. -A number of title compounds like (I)-(III) are prepared. They show modest inhibitory activity for HIV-1 protease. -(MURPHY*, P. V.; O'BRIEN, J. L.; GOREY-FERET, L. J.; SMITH, A. B. I.; Tetrahedron 59 (2003) 13, 2259-2271; Dep. Chem., Univ. Coll., Belfield, Dublin 4, Ire.; Eng.) -Jannicke 29-156