INTRODUCTIONA focal point in contemporary research aimed at preventing the heterosexual spread of AIDS has been the development of intravaginal anti-HIV microbicides to curb the mucosal human immunodeficiency virus type 1 (HIV-1) transmission.AREAS COVEREDThis article reviews the preclinical activity and safety profile of the thiophene thiourea PETT derivative, HI-443 (N'-[2-(2-thiophene)ethyl]-N'-[2-(5-bromopyridyl)] thiourea]). HI-443 is a rationally designed non-nucleoside reverse transcriptase inhibitor (NNRTI) with unprecedented activity against primary clinical HIV-1 isolates with NRTI or NNRTI resistance, multidrug resistance as well as non-B envelope subtypes of HIV-1. HI-443 exhibited a favorable toxicity and pharmacokinetics profile following oral, intraperitoneal or intravenous administration in rodents and a favorable safety profile after repeated intravaginal dosing via a gel formulation in rabbits and pigs. HI-443 did not induce the secretion of pro-inflammatory cytokines and chemokines by three-dimensional reconstituted human vaginal epithelia integrating Langerhans cells ex vivo or in the in vivo porcine model at therapeutic dose levels. Intravaginally administered HI-443 prevented vaginal transmission of a drug-resistant clinical HIV-1 isolate in the surrogate Hu-PBL-SCID mouse model of AIDS.EXPERT OPINIONThe discovery of HI-443 as a non-spermicidal broad-spectrum antiretroviral agent represents a significant step forward in the development of a prophylactic microbicide without contraceptive activity for curbing heterosexual HIV transmission.

01 Feb 2001·Bioorganic & Medicinal Chemistry LettersQ4 · MEDICINE

Anti-HIV activity of aromatic and heterocyclic Thiazolyl Thiourea compounds

Q4 · MEDICINE

Article

Author: T.K. Venkatachalam ; Fatih M. Uckun ; Chen Mao ; Elise A. Sudbeck

Several thiazolyl thiourea derivatives were designed and synthesized as non-nucleoside inhibitors (NNRTI) of HIV-1 reverse transcriptase. Six lead compounds were identified that showed subnanomolar IC50 values for the inhibition of HIV replication, were minimally toxic to human peripheral blood mononuclear cells (PBMC) with CC50 values ranging from 28 to >100 microM, and showed remarkably high selectivity indices ranging from 28,000 to >100,000. The most promising compound was N-[1-(1-furoylmethyl)]-N'-[2-(thiazolyl)]thiourea (compound 6), which showed potency against two NNRTI-resistant HIV-1 isolates (A17 and A17 variant) at nanomolar to low micromolar concentrations, exhibited much greater potency against both wild-type as well as NNRTI-resistant HIV-1 than nevirapine, delavirdine, HI-443, and HI-244, was minimally toxic to PBMC, and had a selectivity index of > 100,000. The potency and minimal cytotoxicity of these aromatic/heterocyclic thiourea compounds suggest that they may be potentially useful as anti-AIDS drugs.

01 Nov 2000·Biochemical PharmacologyQ2 · MEDICINE

Structure-based drug design of non-nucleoside inhibitors for wild-type and drug-resistant HIV reverse transcriptase

Q2 · MEDICINE

Review

Author: T.K Venkatachalam ; Fatih M Uckun ; Elise A Sudbeck ; Chen Mao

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.

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Indication	Highest Phase	Country/Location	Organization	Date
HIV Infections	Preclinical	US	-	-

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