CONFERENCE REPORTS 295

CHIMIA 1999. 53. NO.6

CONFERENCE REPORTS

Chimia 53 (1999) 295-304 © Neue Schweizerische Chemische Gesellschaft ISSN 0009-4293

Second Swiss/German Meeting on Medicinal Chemistry

Fruhjahrsversammlung 1999 der Neuen Schweizerischen Chemischen Gesellschaft (NSCG) 22./23. Marz 1999, Basel

Vier Mini-Symposia uber Virologie, Multidrug Resistance, Immunologie und Gene Therapie

Organisiert von der Sektion Medizinische Ghemie der NSGG, der Fachgruppe fUr Medizinische Chemie der GDGh und der Basler Chemischen Gesellschatt mit Unterstutzung der Pharmazeutischen Industrie.

Report by the Research Team of G. Folkers' 'Correspondence: Prof. Dr. G. Folkers Department of Pharmacy Winterthurerstrasse 190 CH-8057Zi.irich E-Mail: [email protected]

Discovery of Indinavir and Efavirenz, New Therapeutic Agents for AIDS

Terry A. Lyle, Merck Research Laboratories, West Point, PA, USA

For the treatment of HIV infection, two enzymes are of major interest: The HIV-l Protease (PR) and the Reverse- Tran- scriptase (RT). The HIV -Protease, an aspartic-acid pro- tease active as a dimer, is responsible for H 0 the cleavage of polypeptides assembled at o N~' the cell membrane. The inhibition of the Y I( ; N 1\ 0 = H protease-mediated cleavage of the viral "0 o o o precursor polyproteins results in the pro- duction of noninfectious progeny viral par- ticles. The development of lndinavir start- ed with screening a collection of renin inhibitors. A seven-amino-acid analog 1 1 which contains the hydroxyethylene tran- CONFERENCE REPORTS 296

CHIMIA 1999, 53. No.6

prevents the spread of the virus. Different nucleoside inhibitors like AZT, ddI, ddC, d4T and 3TC are already known, but new QH non-nucleoside inhibitors (NNRTI) are U'O developed to decrease the cytotoxicity and N : to improve the selectivity of the viral polymerases vs. mammalian ones. OANH The identification of new lead com- pounds was accomplished using an assay measuring the incorporation of 3H-dGTP +2 into rCdG. The screening was carried out with the Merck sample collection contain- ing about 105 compounds. Initial lead com- pounds from the pyridinone class showed a rapid drop in vRNA but also a rapid emergence of resistant viruses. Further lead structures were thiourea compounds CI CI with lC50(rCdG) = 60 nM (3). The intro- duction of a smaller alkyl group at C(4) improved the activity to lC50(rCdG) = 8 nM .The problem of these compounds was the reactivity and the toxicity. Their oxo- 3 4 analogues with a cyclopropyl group at C(4) and different alkyl substituents were synthesized (4). All compounds exhibited a low bioa- tional introduction of a hydroxy group cis vailability, except the compound with a 4- to the amino functionality increased the acetylene functionality (lC50(rCdG) = 30 activity to a subnanomolar range (lC50 = nM). By incorporating an aryl group onto 0.3 nM). To improve the water solubility, the end of the 4-acetylene functionality, different compounds were designed by the requirement for a metabolically labile molecular modeling. The introduction of 3-methyl group on the dihydroquinazo- a morpholinoethoxy group in the PI' phe- linone nucleus was eliminated. The de- nyl position gave an increase of the solu- methylated compound showed approxi- bility buta lower activity (lCso = 0.45 nM). mately the same activity and an increase in Due to the low bioavailability of the new bioavailability. compound (only 3-5% in dogs and rats), To prevent metabolic methylation, the 5 new modifications were developed. The nitrogen was replaced by an oxygen giv- replacement of the Boc-Phe portion by a ing benzoxazinone derivatives. A mem- decahydroisoquinolineamine and the ex- ber of this class, compound L-743,726 sition-state isostere was identified as a ploration of further isosteres of this deca- (Efavirenz, 5), was found to be a potent potent inhibitor of PR: hydroisoquinoline group finally led to a inhibitor of the wild-type RT (Kj = 2.93 The potency was characterized by N4-substituted piperazine compound (Indi- nM, CIC95 = 1.5 nM). This compound was measuring lC50 and CIC95 values. This navir, 2) with good oral bioavailability in also found to be capable of inhibiting a compound served as starting-point for dif- three different animal species. panel of NNRTI-resistant mutant viruses ferent modifications. The binding to the The new potent protease inhibitor was with CIC95 ~ 1.5 )..!M. protease is stereoselective and requires tested in combination with other antiretro- In the triple therapy (EFV +ZDV +3TC), the absolute configuration at the hydroxy- viral drugs and showed a profound and statistically significant differences were C(4) and PI '-substituted C(2) C-atoms to sustained suppression of HI V replication. observed vs. standard triple therapy (IDV + be (S) and (R), respectively. The deletion The decrease in HIV RNA over the first 24 ZDV +3TC) in terms of higher percentage of the N-terminal two amino-acid residues weeks was greater in the three-drug group of patients with lower levels than 400 (-Phe-Phe) led to a more potent inhibitor than in the other groups. The increase in vRNA copies per ml during the first 24 of PR which had lost its activity against CD4-cell counts over the first 24 weeks weeks. The mean change of CD4 counts renin. The replacement of the C-terminal was greater in the two groups receiving from baseline at 36 weeks was approxi- leucylphenylalanylamide dipeptide by a Indinavir than in the Zidovudine-Lamivu- mately the same as in standard triple ther- benzyl amide afforded an inhibitor retain- dine group. The changes in the viral load apy. ing inhibitory activity against PR. The and the CD4-cell count persisted for up to benefit of this approach was the reduction 52 weeks. of the molecular weight and the elimina- The second enzyme of interest is the tion of several peptide bonds diminishing HIV -1 reverse transcriptase (RT) which the potential for recognition by degrada- consists of the two subunits p66 and pSI tive proteases in vivo. The replacement of and acts as polymerase and RNase respon- the benzylamide by an indane moiety in- sible for the transcription of viral ssRNA creased the activity to lC50 = 26 nM. Addi- to dsDNA. The inhibition of this enzyme