Tricyclic HIV integrase inhibitors: VI. SAR studies of 'benzyl flipped' C3-substituted pyrroloquinolines

Bioorganic and Medicinal Chemistry Letters

Volumn 19, Issue 4, 2009, Pages 1187-1190

  Metobo, Sammy ^a   Mish, Michael ^a   Jin, Haolun ^a   Jabri, Salman ^a   Lansdown, Rachael ^a   Chen, Xiaowu ^a   Tsiang, Manuel ^a   Wright, Matthew ^a   Kim, Choung U ^a  

^a GILEAD SCIENCES   (United States)

Author keywords

AIDS; C3 Benzyl SAR; HIV; Integase inhibitors; Tricyclic pyrroloquinoline

Indexed keywords

BENZYL DERIVATIVE; INTEGRASE INHIBITOR; POLYCYCLIC AROMATIC HYDROCARBON DERIVATIVE; PYRROLOQUINOLINEQUINONE; RALTEGRAVIR;

ACQUIRED IMMUNE DEFICIENCY SYNDROME; ANIMAL EXPERIMENT; ANIMAL MODEL; ANTIVIRAL ACTIVITY; ARTICLE; CONTROLLED STUDY; DRUG BIOAVAILABILITY; DRUG HALF LIFE; DRUG POTENCY; DRUG SYNTHESIS; HUMAN IMMUNODEFICIENCY VIRUS; NONHUMAN; RAT; STRUCTURE ACTIVITY RELATION;

ADMINISTRATION, ORAL; ANIMALS; ANTI-HIV AGENTS; DOGS; DRUG DESIGN; HIV INTEGRASE INHIBITORS; HUMANS; MOLECULAR STRUCTURE; PYRROLES; QUINOLINES; RATS; STRUCTURE-ACTIVITY RELATIONSHIP;

ANIMALIA;

EID: 59649100515     PISSN: 0960894X     EISSN: None     Source Type: Journal    
DOI: 10.1016/j.bmcl.2008.12.079     Document Type: Article

References (9)

1. To date, only a single HIV integrase inhibitor, MK-0518 (Raltegravir), has gained FDA approval for marketing in the US, while many others continue to advance through late-stage human clinical trials. See:. Summa V., Petrocchi A., Bonelli F., Benedetta Crescenzi B., Donghi M., Ferrara M., Fiore F., Gardelli C., Gonzalez Paz O., Hazuda D.J., Jones P., Kinzel O., †Laufer R., Monteagudo E., Muraglia E., Nizi E., Orvieto F., Pace P., Pescatore G., Scarpelli R., Stillmock K., Witmer M.V., and Michael Rowley M. J. Med. Chem. 513 (2008) 5843
2. Jin H., Cai R.Z., Schacherer L., Jabri S., Tsiang M., Fardis M., Chen X., Chen J.M., and Kim C.U. Bioorg. Med. Chem. Lett. 16 (2006) 3989 and the references cited within
3. Fardis M., Jin H., Jabri S., Cai R.Z., Mish M., Tsiang M., and Kim C.U. Bioorg. Med. Chem. Lett. 16 (2006) 4031
4. Metobo S., Jin H., Tsiang M., and Kim C.U. Bioorg. Med. Chem. Lett. 16 (2006) 3985
5. Jin H., Wright M., Pastor R., Mish M., Metobo S., Jabri S., Lansdown R., Cai R.Z., Pyun P., Tsiang M., Chen X., and Kim C.U. Bioorg. Med. Chem. Lett. 16 (2008) 3989
6. Chen X., Tsiang M., Yu F., Hung M., Jones G.S., Zeynalzadegan A., Qi X., Jin H., Kim C.U., Swaminathan S., and Chen J.M. J. Mol. Biol. 380 (2008) 504 and references cited therein
7. The preparation of pyridine dielectrophile 3 has been reported in Johns, B.; Boros, E.; Kawasuji, T.; Koble, C. S.; Kurose, N.; Murai, H.; Sherrill, R.; Weatherhead, J. W.O. Patent 2005/077050(A2), 2005, while the preparation of pyridines 12 and 13 is based on chemistry reported in Cai, Z.; Jabri, S.; Jin, H.; Lansdown, R.; Metobo, S.; Mish, M.; Pastor, R. W.O. Patent 2007/136714(A2), 2007.
8. 50 of compound 11 alongside either 9, or a related inhibitor originally reported in Ref. 2a wherein the bulky C3-p-fluorobenzyl substituent of 11 is replaced with a proton, illustrates a large decrease in the potency of 11 compared to either of these nearly identical analogs that carry only a single benzyl tail group.
9. 50 resulting from the combined effect of both proteins (as in serum) can be calculated. The derivation of the appropriate equation for this calculation can be made through competitive binding assumptions.