The generation of anti-HIV agents using structure-based drug design methods has yielded a number of promising non-nucleoside inhibitors (NNIs) of HIV reverse transcriptase (RT). Recent successes in identifying potent NNIs are reviewed with an emphasis on the recent trend of utilizing a computer model of HIV RT to identify space in the NNI binding pocket that can be exploited by carefully chosen functional groups predicted to interact favorably with binding pocket residues. The NNI binding pocket model was used to design potent NNIs against both wild-type RT and drug-resistant RT mutants. Molecular modeling and score functions were used to analyze how drug-resistant mutations would change the RT binding pocket shape, volume, and chemical make-up, and how these changes could affect inhibitor binding. Modeling studies revealed that for an NNI of HIV RT to be active against RT mutants such as the especially problematic Y181C RT mutant, the following features are required: (a) the inhibitor should be highly potent against wild-type RT and therefore capable of tolerating a considerable activity loss against RT mutants (i.e. a picomolar-level inhibitor against wild-type RT may still be effective against RT mutants at nanomolar concentrations), (b) the inhibitor should maximize the occupancy in the Wing 2 region of the NNI binding site of RT, and (c) the inhibitor should contain functional groups that provide favorable chemical interactions with Wing 2 residues of wild-type as well as mutant RT. Our rationally designed NNI compounds HI-236, HI-240, HI-244, HI-253, HI-443, and HI-445 combine these three features and outperform other anti-HIV agents examined.

01 Sep 1999·Bioorganic & Medicinal Chemistry LettersQ4 · MEDICINE

N-[2-(1-cyclohexenyl)ethyl]-N′-[2-(5-bromopyridyl)]-thiourea and N′-[2-(1-cyclohexenyl)ethyl]-N′-[2-(5-chloropyridyl)]- thiourea as potent inhibitors of multidrug-resistant human immunodeficiency virus-1

Q4 · MEDICINE

Article

Author: Dan Zhu ; T.K. Venkatachalam ; Lisa Tuel-Ahlgren ; Chen Mao ; Danielle Maher ; Sharon Pendergrass ; Fatih M. Uckun

We have replaced the pyridyl ring of trovirdine with an alicyclic cyclohexenyl, adamantyl or cis-myrtanyl ring. Only the cyclohexenyl-containing thiourea compound N-[2-(1-cyclohexenyl)ethyl]-N'-[2-(5-bromopyridyl)]- thiourea (HI-346) (as well as its chlorine-substituted derivative N-[2-(1-cyclohexenyl)ethyl]-N'-[2-(5-chloropyridyl)]- thiourea/HI-445) showed RT inhibitory activity. HI-346 and HI-445 effectively inhibited recombinant RT with better IC50 values than other anti-HIV agents tested. The ranking order of efficacy in cell-free RT inhibition assays was: HI-346 (IC50 = 0.4 microM) > HI-445 (IC50 = 0.5 microM) > trovirdine (IC50 = 0.8 microM) > MKC-442 (IC5 = 0.8 microM) = delavirdine (IC50 = 1.5 microM) > nevirapine (IC50 = 23 microM). In accord with this data, both compounds inhibited the replication of the drug-sensitive HIV-1 strain HTLV(IIIB) with better IC50 values than other anti-HIV agents tested. The ranking order of efficacy in cellular HIV-1 inhibition assays was: HI-445 = HI-346 (IC50 = 3 nM) > MKC-442 (IC50 = 4 nM) = AZT (IC50 = 4 nM) > trovirdine (IC50 = 7 nM) > delavirdine (IC50 = 9 nM) > nevirapine (IC50 = 34 nM). Surprisingly, the lead compounds HI-346 and HI-445 were 3-times more effective against the multidrug resistant HIV-1 strain RT-MDR with a V106A mutation (as well as additional mutations involving the RT residues 74V,41L, and 215Y) than they were against HTLV(IIIB) with wild-type RT. HI-346 and HI-445 were 20-times more potent than trovirdine, 200-times more potent than AZT, 300-times more potent than MKC-442, 400-times more potent than delavirdine, and 5000-times more potent than nevirapine against the multidrug resistant HIV-1 strain RT-MDR. HI-445 was also tested against the RT Y181C mutant A17 strain of HIV-1 and found to be >7-fold more effective than trovirdine and >1,400-fold more effective than nevirapine or delavirdine. Similarly, both HI-346 and HI-445 were more effective than trovirdine, nevirapine, and delavirdine against the problematic NNI-resistant HIV-1 strain A17-variant with both Y181C and K103N mutations in RT, although their activity was markedly reduced against this strain. Neither compound exhibited significant cytotoxicity at effective concentrations (CC50 >100 microM). These findings establish the lead compounds HI-346 and HI-445 as potent inhibitors of drug-sensitive as well as multidrug-resistant stains of HIV-1.

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Indication	Highest Phase	Country/Location	Organization	Date
HIV Infections	Discovery	US	The Howard Hughes Medical Institute	-

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