Discovery and synthesis of HIV integrase inhibitors: development of potent and orally bioavailable N-methyl pyrimidones.
The human immunodeficiency virus type-1 (HIV-1) encodes three enzymes essential for viral replication: a reverse transcriptase, a protease, and an integrase. The latter is responsible for the integration of the viral genome into the human genome and, therefore, represents an attractive target for chemotherapeutic intervention against AIDS. A drug based on this mechanism has not yet been approved. Benzyl-dihydroxypyrimidine-carboxamides were discovered in our laboratories as a novel and metabolically stable class of agents that exhibits potent inhibition of the HIV integrase strand transfer step. Further efforts led to very potent compounds based on the structurally related N-Me pyrimidone scaffold. One of the more interesting compounds in this series is the 2-N-Me-morpholino derivative 27a, which shows a CIC95 of 65 nM in the cell in the presence of serum. The compound has favorable pharmacokinetic properties in three preclinical species and shows no liabilities in several counterscreening assays.
Gardelli
Cristina
C
Department of Medicinal Chemistry - Istituto Di Ricerche Di Biologia Molecolare, P. Angeletti S.p.A. (IRBM-MRL Rome), Via Pontina Km 30,600, 00040 Pomezia, Italy. cristina_gardelli@merck.com
Nizi
Emanuela
E
Muraglia
Ester
E
Crescenzi
Benedetta
B
Ferrara
Marco
M
Orvieto
Federica
F
Pace
Paola
P
Pescatore
Giovanna
G
Poma
Marco
M
Ferreira
Maria Del Rosario Rico
Mdel R
Scarpelli
Rita
R
Homnick
Carl F
CF
Ikemoto
Norihiro
N
Alfieri
Anna
A
Verdirame
Maria
M
Bonelli
Fabio
F
Paz
Odalys Gonzalez
OG
Taliani
Marina
M
Monteagudo
Edith
E
Pesci
Silvia
S
Laufer
Ralph
R
Felock
Peter
P
Stillmock
Kara A
KA
Hazuda
Daria
D
Rowley
Michael
M
Summa
Vincenzo
V
D000284:Administration, Oral; D000818:Animals; D001682:Biological Availability; D001798:Blood Proteins / Q000378:metabolism; D045744:Cell Line, Tumor; D004285:Dogs; D019427:HIV Integrase / Q000737:chemistry*; D019428:HIV Integrase Inhibitors / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D015497:HIV-1 / Q000187:drug effects* / Q000201:enzymology / Q000502:physiology; D006801:Humans; D008253:Macaca mulatta; D009025:Morpholines / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D011485:Protein Binding; D011744:Pyrimidinones / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D051381:Rats; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D014779:Virus Replication / Q000187:drug effects