In vivo pharmacokinetics, metabolism, toxicity, and anti-HIV activity of N'-[2-(2-Thiophene)ethyl]-N'-[2-(5-bromopyridyl)]thiourea (HI-443), a potent non-nucleoside inhibitor of HIV reverse transcriptase.

N'-[2-(2-Thiophene)ethyl]-N'-[2-(5bromopyridyl)]thiourea (CAS 258340-15-7, HI-443) is a potent non-nucleoside inhibitor of HIV reverse transcriptase (NNRTI) that was rationally designed as a candidate anti-HIV agent. The purpose of the present study was to examine the in vivo pharmacokinetics, metabolism, toxicity, and anti-HIV activity of HI-443. HI-443 was very well tolerated in CD-1 mice and Lewis rats without any detectable toxicity at single parenteral bolus dose levels as high as 80 mg/kg.

Effect of targeting janus kinase 3 on the development of intestinal tumors in the adenomatous polyposis coli(min) mouse model of familial adenomatous polyposis.

Familial adenomatous polyposis (FAP) is associated with germ-line mutations in the tumor suppressor gene, adenomatous polyposis coli (APC) located on chromosome 5q21. Multiple intestinal neoplasia (Min) in mice resembles FAP in humans, resulting from a single point mutation in the murine homolog of the APC gene. The effects of the rationally-designed Janus kinase 3 (JAK3) inhibitor JANEX-1 (4-(4'-hydroxyphenyl) amino-6,7-dimethoxy-quinazoline, WHI-P131, CAS 202475-60-3) on the development of intestinal tumors in the APC (min/+) mouse model of FAP were examined.

In vivo pharmacokinetics and toxicity of a novel hydrophilic oral formulation of the potent non-nucleoside reverse transcriptase inhibitor compound N'-[2-(2-thiophene)ethyl]-N'-[2-(5-bromopyridyl)]-thiourea (HI-443).

The thiophene ethyl thiourea (TET) compound N'-[2-(2-thiophene)ethyl]-N'-[2-(5-bromopyridyl)]-thiourea (HI-443) is a potent non-nucleoside reverse transcriptase inhibitor (NNRTI). The pharmacokinetics of 17 different novel oral formulations of HI-443 were compared in an attempt to identify the most suitable dosage form for clinical use in HIV-infected persons. Plasma concentrations of HI-443 were monitored in mice after administration of the drug using these 17 different formulations at three time points.

Improved oral bioavailability of anti-HIV agent N'-[2-(2-thiophene)ethyl]-N'-[2-(5-bromopyridyl)]-thiourea (HI-443) in a novel lipophilic formulation.

N'-[2-(2-Thiophene)ethyl]-N'-[2-(5-bromopyridyl)]-thiourea (CAS 258340-15-7, HI-443) is a rationally designed non-nucleoside reverse transcriptase inhibitor (NNRTI) with potent anti-HIV activity at nanomolar concentrations but poor oral bioavailability. Here the identification of a novel oleic acid containing lead formulation of HI-443 is described which resulted in a approximately 10-fold improvement of its oral bioavailability yielding 10-fold higher systemic exposure levels in mice. Formulated HI-443 exhibited a favorable pharmacokinetics and toxicity profile in mice.

Preclinical toxicity and pharmacokinetics of the Bruton's tyrosine kinase-targeting anti-leukemic drug candidate, alpha-cyano-beta-hydroxy-beta-methyl-N- (2,5-dibromophenyl) propenamide (LFM-A13).

The leflunomide (CAS 75706-12-6) metabolite (LFM) analog alpha-cyano-beta-hydroxy-beta-methyl-N-(2,5-dibromophenyl)-propenamide (LFM-A13, DDE-28, CAS 244240-24-2) is a rationally-designed specific inhibitor of the TEC family protein tyrosine kinase, Bruton's tyrosine kinase (BTK). LFM-A13 exhibited favorable pharmacokinetics in CD-1 mice, BALB/c mice, rats, and dogs. The intraperitoneal bioavailability was estimated to be -100%, while the oral bioavailability was -30%.

Developmental safety profile of the anti-HIV agent stampidine in rabbits.

Stampidine (STAMP, DDE-113, HI-113, N-[p-(4-bromophenyl)-2',3'-didehydro-3'-deoxy-5'-thymidylyl]-L-alanine methyl ester, CAS 217178-62-6) is a novel aryl phosphate derivative of stavudine (STV, d4T, 2',3'-didehydro-3'-deoxythymidine, CAS 3056-17-5) with potent anti-HIV activity. The reproductive and developmental safety profile of STAMP was evaluated in mated New Zealand white rabbits. STAMP did not adversely affect the reproductive health of female rabbits and it lacked teratogenicity or other developmental toxicity in their progeny.

A study of the potential of the pig as a model for the vaginal irritancy of benzalkonium chloride in comparison to the nonirritant microbicide PHI-443 and the spermicide vanadocene dithiocarbamate.

A porcine model was established to test the mucosal toxicity potential of a thiophene thiourea (PHI-443)-based anti-HIV microbicide and a vanadocene-based spermicide, vanadocene dithiocarbamate (VDDTC) in comparison to benzalkonium chloride (BZK). Nine domestic pigs (Duroc) in nonestrus stage received a single intravaginal application of 2% BZK, 2% PHI-443, or 0.1% VDDTC-containing gel.

Anti-cancer activity profile of 3'-azidothymidine 5'-[p-methoxyphenyl methoxyalaninyl phosphate] (Compound 003), a novel nucleoside analog.

The novel cytotoxic nucleoside analog Compound 003 (3'-azidothymidine 5'-[p-methoxyphenyl methoxyalaninyl phosphate], CAS 149560-32-7) prevented bipolar mitotic spindle assembly and caused a G2 arrest in human cancer cells. Compound 003 was very well tolerated by both mice and rats without any toxicity at cumulative dose levels >2 g/kg. Notably, Compound 003 prolonged cancer-free survival in the MMTVneu transgenic mouse model of HER2 positive breast cancer.

Developmental toxicology studies of WHI-07, a novel nucleoside analogue-based dual-function microbicide, administered intravaginally to rabbits.

The zidovudine derivative, 5-bromo-6-methoxy-5,6-dihydro-3-azidothymidine-5'-(p-bromophenyl) methoxy alaninyl phosphate (WHI-07), is a dual-function spermicidal and anti-HIV agent with contraceptive and microbicidal activity. In previous subchronic and reproductive toxicity studies and a two-year carcinogenicity study, daily intravaginal application of 0.5 to 2.

Toxicity and pharmacokinetics of stampidine in mice and rats.

The in vivo toxicity and pharmacokinetics of stampidine (CAS 217178-62-6), an aryl phosphate derivative of stavudine (CAS 3056-17-5) under development as a new anti-human immunodeficiency virus (anti-HIV) agent, were studied in mice and rats. Stampide was very well tolerated by both mice and rats without any toxicity at cumulative dose levels > 1 g/kg. Therapeutic micromolar plasma concentrations of stampidine and its active metabolites ala-STV-MP (CAS 180076-92-0) and STV were rapidly achieved and maintained several hours after i.

Two-year toxicity and carcinogenicity studies in B(6)C(3)F(1) mice with 5-bromo-6-methoxy-5,6-dihydro-3'-azidothymidine-5'-(p-bromophenyl) methoxyalaninyl phosphate (WHI-07), a novel anti-HIV and contraceptive agent.

The zidovudine derivative, 5-bromo-6-methoxy-5,6-dihydro-3'-azidothymidine-5'-(p-bromophenyl) methoxy alaninyl phosphate (WHI-07), is a dual-function spermicidal and anti-HIV agent with contraceptive and microbicidal activity. In previous two subchronic toxicity studies, intravaginal application of 0.5-2.