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UC-781
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Drug Class: Microbicides

Drug Description
UC-781 is a thiocarboxanilide non-nucleoside reverse transcriptase inhibitor (NNRTI).[1]

HIV/AIDS-Related Uses
UC-781 is an NNRTI currently being developed as a vaginal microbicide to prevent HIV transmission. UC-781 has been studied in animal models and has entered a Phase I clinical trial in humans. UC-781 is now in Phase II trials in the United States and in Thailand.[2][3]

Dosing Information

Mode of Delivery
Intravaginal.[4] Rectal.[5]

Dosage Form
Topical gel in 0.1%, 0.25%, or 1.0% concentrations.[6][7] UC-781 has been studied in once-daily dosages for up to 7 days and in twice-daily dosages for up to 14 days.[8][9]

Pharmacology
In vitro studies have shown UC-781 to be a rapid, tight-binding inhibitor of HIV-1 reverse transcriptase.[10] It is effective against transmission of both free-floating HIV particles and cell-associated HIV. UC-781 has an intracellular antiviral protective effect and a half-life of 5.5 days.[11][12]

In vitro exposure of human cervical tissue to UC-781 for 30 minutes has resulted in 95% reduction of subsequent HIV infection. Furthermore, greater concentrations of UC-781 pretreatment have resulted in total protection of the cervical tissue from both X4- and R5-tropic HIV-1 isolates as well as from cell-associated HIV-1 infection. Twenty-minute incubation with UC-781 has completely protected the cervical tissue up to 48 hours post-treatment without associated tissue toxicity.[13]

UC-781 administered to cellular and tissue explant models as a 0.1% carbopol gel formulation has demonstrated a potent, dose-dependent effect against R5- and X4-tropic HIV infections in T cells. In human cervical explant cultures, UC-781 was able to not only inhibit direct infection of mucosal tissue but also to prevent dissemination of virus by migratory cells. UC-781 retained significant activity against direct tissue infection and migratory cell infection. UC-781 demonstrated prolonged inhibitory effects able to prevent both localized and disseminated infections up to 6 days post-treatment. In addition, a 2-hour exposure to UC-781 prevented infection of lymphoid tissue when challenged up to 2 days later. Although a greater dose of UC-781 was required to inhibit infections of lymphoid versus cervical explant, that dose, equivalent to a 1:3.000 dilution, was less than the full dose provided in a 0.1% formulation.[14]

The prolonged protective effect of UC-781, characterized as a memory effect that continues to protect drug-treated cells from HIV-1 replication, has been demonstrated for up to 12 days.[15]

UC-781 has been studied with the nucleoside reverse transcriptase inhibitor (NRTI) zidovudine in vitro. A 1:1 molar combination of zidovudine plus UC-781 showed high-level synergy in inhibiting replication of a zidovudine-resistant clinical isolate of HIV. When a 1:1 molar combination of zidovudine and UC-781 was compared to use of either drug alone, HIV resistance development was significantly slower.[16]

The microbicidal activity of UC-781 has been studied in vitro against strains of HIV-1 resistant to UC-781 (UCR), efavirenz (EFVR), and nevirapine (NVPR). UC-781 was 10- to 100-fold less effective against resistant strains than wild-type virus. The drug was more effective against NVPR strains than UCR strains, and was less effective against EFVR strains than UCR strains. Efficacy of UC-781 was dose-dependent; 25 mcM UC-781 provided essentially equivalent microbicidal activity against NNRTI-resistant and wild-type virus. UC-781 formulations under current development contain concentrations approximately 100-fold greater than the 25 mcM concentration necessary for efficacy.[17]

Drug And Food Interactions
UC-781 exhibits synergy with the NRTI zidovudine in vitro.[18] The combination of UC-781 and another candidate microbicide, cellulose acetate 1,2-benzenedicarboxylate, resulted in effective synergy for inhibition of HIV-1 in vitro and in peripheral blood mononuclear cells. Concomitant administration provided complementary mechanisms of action and protected ex vivo lymphoid tissues from HIV infection.[19]

Clinical Trials
Click here to search ClinicalTrials.gov for trials that use UC-781.

Chemistry

CAS Name
3-Furancarbothioamide, N-(4-chloro-3-((3-methyl-2-butenyl)oxy)phenyl)-2-methyl-[20]

CAS Number
178870-32-1[21]

Molecular Formula
C17-H18-Cl-N-O2-S[22]

Elemental Composition
C60.8%, H5.4%, Cl10.6%, N4.2%, O9.5%, S9.5%[23]

Molecular Weight
335.5[24]

Further Reading
PMID/15855503 Liu S, Lu H, Neurath AR, Jiang S. Combination of candidate microbicides cellulose acetate 1,2-benzenedicarboxylate and UC-781 has synergistic and complementary effects against human immunodeficiency virus type 1 infection. Antimicrob Agents Chemother. 2005 May;49(5):1830-6.

PMID/17353420 Patton DL, Sweeney YT, Balkus JE, Rohan LC, Moncla BJ, Parniak MA, Hillier SL. Preclinical safety assessments of UC-781 anti-human immunodeficiency virus topical microbicide formulations. Antimicrob Agents Chemother. 2007 May;51(5):1608-15.

PMID/17404008 Roth S, Monsour M, Dowland A, Guenthner PC, Hancock K, Ou CY, Dezzutti CS. Effect of topical microbicides on infectious human immunodeficiency virus type 1 binding to epithelial cells. Antimicrob Agents Chemother. 2007 Jun;51(6):1972-8.

PMID/17922539 Sassi AB, Isaacs CE, Moncla BJ, Gupta P, Hillier SL, Rohan LC. Effects of physiological fluids on physical-chemical characteristics and activity of topical vaginal microbicide products. J Pharm Sci. 2007 Oct 5 [Epub ahead of print].

PMID/14693562 Van Herrewege Y, Michiels J, Van Roey J, Fransen K, Kestens L, Balzarini J, Lewi P, Vanham G, Janssen P. In vitro evaluation of nonnucleoside reverse transcriptase inhibitors UC-781 and TMC120-R147681 as human immunodeficiency virus microbicides. Antimicrob Agents Chemother. 2004 Jan;48(1):337-9.

ClinicalTrals.gov- Phase I Study of Safety and Persistence of UC-781 Vaginal Microbicide. Available at: http://www.clinicaltrials.gov/ct2/show/NCT00441909?term=NCT00441909&rank=1. Accessed 02/12/08.

Manufacturer Information
UC-781
  Cellegy Pharmaceuticals, Inc
  3490 Oyster Point Boulevard
  Suite 200
  South San Francisco,  CA  94080
  (650) 616-2200
    

References
[1] J Virol - 2005;79(17):11179-86
[2] CONRAD - New Licensing Agreement to Maximize AIDS Drug Development [press release], February 1, 2006. Available at: http://www.conrad.org/press/02012006.htm. Accessed 2/12/08.
[3] ClinicalTrials.gov - Study of UC-781 Vaginal Microbicide. Available at: http://www.clinicaltrials.gov/ct/show/NCT00132444. Accessed 2/12/08.
[4] ClinicalTrials.gov - Study of UC-781 Vaginal Microbicide. Available at: http://www.clinicaltrials.gov/ct/show/NCT00132444. Accessed 2/12/08.
[5] ClinicalTrials.gov - Safety and Acceptability Study of the UC-781 Microbicide Gel Applied Rectally. Available at: http://www.clinicaltrials.gov/ct2/show/NCT00408538. Accessed 2/12/08.
[6] Microbicides Conference - 2nd, 2006. Abstract PA58.
[7] ClinicalTrials.gov - Study of UC-781 Vaginal Microbicide. Available at: http://www.clinicaltrials.gov/ct/show/NCT00132444. Accessed 2/12/08.
[8] ClinicalTrials.gov - Study of UC-781 Vaginal Microbicide. Available at: http://www.clinicaltrials.gov/ct/show/NCT00132444. Accessed 2/12/08.
[9] ClinicalTrials.gov - Safety and Acceptability Study of the UC-781 Microbicide Gel Applied Rectally. Available at: http://www.clinicaltrials.gov/ct2/show/NCT00408538. Accessed 2/12/08.
[10] Antimicrob Agents Chemother - 2005 May;49(5):1830-6
[11] J Virol - 1997 Apr;71(4):3023-30
[12] AIDS - 2003 Mar 28;17(5):653-61
[13] Conf Retroviruses Opportunistic Infect - 9th, 2002. Abstract 780-W.
[14] J Virol - 2005 Sep;79(17):11179-86
[15] Microbicides Conference - 1st, 2004. Abstract 02460.
[16] Antimicrob Agents Chemother - 1999 Feb;43(2):259-63
[17] J Virol - 2006 May;80:4440-6
[18] Antimicrob Agents Chemother - 1999 Feb;43(2):259-63
[19] Antimicrob Agents Chemother - 2005;49(5):1830-6
[20] ChemIDplus - Available at: http://chem.sis.nlm.nih.gov/chemidplus/chemidlite.jsp. Accessed 2/12/08.
[21] ChemIDplus - Available at: http://chem.sis.nlm.nih.gov/chemidplus/chemidlite.jsp. Accessed 12/08/06.
[22] ChemIDplus - Available at: http://chem.sis.nlm.nih.gov/chemidplus/chemidlite.jsp. Accessed 2/12/08.
[23] Calculation. -
[24] Calculation. -
Updated February 12, 2008