Nonpeptidic HIV protease inhibitors possessing excellent antiviral activities and therapeutic indices. PD 178390: A lead HIV protease inhibitor

With the insight generated by the availability of X-ray crystal structures of various 5,6-dihydropyran-2-ones bound to HIV PR, inhibitors possessing v arious alkyl groups at the 6-position of 5,6-dihydropyran-2-one ring were s ynthesized. The inhibitors possessing a 6-alkyl group exhibited superior an tiviral activities when compared to 6-phenyl analogues. Antiviral efficacie s were further improved upon introduction of a polar group (hydroxyl or ami no) on the 4-position of the phenethyl moiety as well as the polar group (h ydroxymethyl) on the 3-(tert-butyl-5-methyl-phenylthio) moiety. The polar s ubstitution is also advantageous for decreasing toxicity, providing inhibit ors with higher therapeutic indices, The best inhibitor among this series, (S)-6-[2-(4-aminophenyl)-ethyl]-(3-(2-tert-butyl-5-methyl-phenylsulfanyl)-4 -hydroxy-6-isopropyl-5,6-dihydro-pyran-2-one (34S), exhibited an EC50 of 20 0 nM with a therapeutic index of >1000. More importantly, these non-peptidi c inhibitors, 16S and 34S, appear to offer little cross-resistance to the c urrently marketed peptidomimetic PR inhibitors. The selected inhibitors tes ted in vitro against mutant HIV PR showed a very small increase in binding affinities relative to wild-type HIV PR. C-max and absolute bioavailability of 34S were higher and half-life and time above EC95 were longer compared to 16S. Thus 34S, also known as PD 178390, which displays good antiviral ef ficacy, promising pharmacokinetic characteristics and favorable activity ag ainst mutant enzymes and CYP3A4, has been chosen for further preclinical ev aluation. (C) 1999 Elsevier Science Ltd. All rights reserved.