1505
J. Med. Chem. 1993,36, 1505-1508
Bis(heteroary1)piperazine (BHAP) Reverse Transcriptase Inhibitors: Structure-Activity Relationships of Novel Substituted Indole Analogues and the Identification of 1-[ (5-Methanesulfonamido-1H-indol-2-yl)carbonyl]-4-[3-[ (l-methylethyl)amino]pyridinyl]piperazine Monomethanesulfonate (U-90152S),a Second-Generation Clinical Candidate Donna L. Romero,*gtRaymond A. Morge,t Michael J. Genin,+ Carolyn Biles,+Mariano Busso,$ Lionel Resnick,t Irene W. Althaus,t Fritz Reusser,+ Richard C. Thomas,? and William G. Tarpleyt Upjohn Laboratories, Kalamazoo, Michigan 49001, a n d Mount Sinai Medical Center of Greater Miami, Miami Beach, Florida 33140 Received December 10, 1992
Retroviruses such as human immunodeficiency virus type 1(HIV-1) contain an enzyme, reverse transcriptase (RT),which catalyzes the conversion of the genomic viral RNA into the proviral DNA. This process of reverse transcription is an essential step in the life cycle of HIV-1 and is absolutely required for viral rep1ication.l For this reason, the enzyme reverse transcriptase is an ideal target for the development of therapeutics for the treatment of HIV infection. Reverse transcriptase inhibitors (RTIs) such as 3'-azido3'-deoxythymidine (AZT)2and 2',3'-dideoxyinosine (ddI)3 are nucleoside drugs which mimic the normal deoxynucleoside triphosphate substrates for R T and act as chain terminators. Since these drugs have been shown to benefit HIV-l-infected patients, they have been approved by the FDA for the treatment of AIDS. Unfortunately, administration of these compounds to patients often causes serious toxic side effects: thought to be due to the inhibition of cellular DNA polymerases (e.g. lack of sele~tivity).~b,3~.~.~ Moreover, treatment with AZT or ddI results in the emergence of resistant viral strains.6 The successful treatment of HIV-1 infection will most likely require the discovery of drugs which inhibit R T via disparate mechanisms, possibly to be administered in combination with one another. In order to maximize the chances of discovering an inhibitor with a mechanism of action different from that of AZT and ddI, we pursued a strategy which targeted the identification of non-nucleoside inhibitors of R T and their subsequent optimization via molecular modification. A recent disclosure from our laboratories described the discovery and preliminary elucidation of the structureactivity relationships (SAR) of the bis(heteroary1)piperazine (BHAP) class of RT inhibitor^.^ The BHAPs were discoveredvia a computationall9 directed broad screening of the Upjohn chemical repository for R T inhibitors. Chemical modification of the original lead compound, through incorporation of an indole moiety, resulted in dramatically improved anti-HIV-1 activity and led to the identification of atevirdine mesylate (Table I, 2), which is currently undergoing phase I1 clinical e~aluation.~ +
1
Upjohn Laboratories. Mount Sinai Medical Center of Greater Miami.
Table I. Biological Activities of 5- and 6-Substituted Indole Analogues
NHR
"\Q&" H o
compound X 1 H 2d 5-OCH3 3 5-OH 4d H 5 5-OH 6 5-OCHzPh 7 5-CH3 8 5-NH2 9 6-OCH3 10 6-F 11 6-OCHzPh 12 6-OH 13 6-CN 14 6-CHO nevirapine NA L-697,661 NA
R Et Et Et i-Pr i-PI i-Pr i-Pr i-Pr i-Pr i-Pr i-Pr i-Pr i-Pr i-Pr NA NA
R T inhibition" invitro 5% 100 IC50 rM (PM) 96 4.0 92 5.2 89 2 96 1.2 98 1.3 74 4.3 68 34 94 1 97 1.3 96 4.4 65 37 97 1.2 74 3.9 94 1.4 93 5.5 98 2.7
MT-21 IIIbb EDw (rM) 0.3
