Synthesis of Delavirdine Mesylate

Delavirdine mesylate is a member of the /7w(heteroaryl)piperazine (BHAP) class of nonnucleoside HIV-1 reverse transcriptase inhibitors (Adams et al., 1998 Romero et al., 1993 Romero, 1994). This class of compounds was discovered by Upjohn scientists from a computer-directed dissimilarity analysis of the Pharmacia Upjohn chemical library to select compounds for screening against HIV-1 RT. The result of the in vitro assay (Deibel et al., 1990) is an IC50 of 0.260 p,M, which is comparable to AZT. In accordance with the previous NNRTIs, delavirdine is a noncompetitive inhibitor of reverse transcriptase, and has a synergistic effect with nucleoside transcriptase and protease inhibitors (Chong et al., 1994). 

As the NNRTIs are structurally diverse and yet bind to RT at a common site, the similar occurrence of resistance-conferring mutations is not surprising. As a consequence, the effectiveness of other NNRTIs may be compromised by the emergence of HIV-1 variants caused by a previous NNRTI therapy (Sardana et ah, 1992). Experiments were performed in which HIV-1 strains (JR-CSF or ME) are cultured in human lymphocytes in the presence of partially inhibitory concentrations of delavirdine (Dueweke et al., 1993b). These conditions yield mutants that are 100-fold resistant. In order to determine what mutation(s) occurs, PCR (polymerase chain reaction) amplification and DNA sequence analysis of the RT coding region were applied and indicated that mutation P236L had occurred. Mutations at amino acids 181 or 183, which have been associated with resistance to other NNRTIs, are not detected. 

Additional cell culture experiments are conducted to confirm the sensitization observed with the mutant RTs. Lower concentrations of nevirapine (5-20-fold) are 

Investigation of the in vitro metabolism of delavirdine is accomplished using mouse, rat, dog, monkey, rabbit, and human liver microsomes. The primary metabolite observed is the A-dealkylated delavirdine 26. Another primary metabohte observed is the hydroxy-lation of the pyridine ring at C-6 (compound 27). The primary metabolism is by CYP3A4 and also CYP2D6. Delavirdine reduces the activity of CYP3A4, thereby inhibiting its own metabolism. 

Bacheler, L., Weislow, O., Snyder, S., Hanna, G., D Aquila, R. and the SUSTIVA Resistance Study Team (1998). Abstract presented at the 12th World AIDS Conference. 

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