title: Discovery and synthesis of HIV integrase inhibitors: development of potent and orally bioavailable N-methyl pyrimidones.
abstract: 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.
authors.affiliation: 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
authors.forename: Cristina
authors.initials: C
authors.lastname: Gardelli
authors.forename: Emanuela
authors.initials: E
authors.lastname: Nizi
authors.forename: Ester
authors.initials: E
authors.lastname: Muraglia
authors.forename: Benedetta
authors.initials: B
authors.lastname: Crescenzi
authors.forename: Marco
authors.initials: M
authors.lastname: Ferrara
authors.forename: Federica
authors.initials: F
authors.lastname: Orvieto
authors.forename: Paola
authors.initials: P
authors.lastname: Pace
authors.forename: Giovanna
authors.initials: G
authors.lastname: Pescatore
authors.forename: Marco
authors.initials: M
authors.lastname: Poma
authors.forename: Maria Del Rosario Rico
authors.initials: Mdel R
authors.lastname: Ferreira
authors.forename: Rita
authors.initials: R
authors.lastname: Scarpelli
authors.forename: Carl F
authors.initials: CF
authors.lastname: Homnick
authors.forename: Norihiro
authors.initials: N
authors.lastname: Ikemoto
authors.forename: Anna
authors.initials: A
authors.lastname: Alfieri
authors.forename: Maria
authors.initials: M
authors.lastname: Verdirame
authors.forename: Fabio
authors.initials: F
authors.lastname: Bonelli
authors.forename: Odalys Gonzalez
authors.initials: OG
authors.lastname: Paz
authors.forename: Marina
authors.initials: M
authors.lastname: Taliani
authors.forename: Edith
authors.initials: E
authors.lastname: Monteagudo
authors.forename: Silvia
authors.initials: S
authors.lastname: Pesci
authors.forename: Ralph
authors.initials: R
authors.lastname: Laufer
authors.forename: Peter
authors.initials: P
authors.lastname: Felock
authors.forename: Kara A
authors.initials: KA
authors.lastname: Stillmock
authors.forename: Daria
authors.initials: D
authors.lastname: Hazuda
authors.forename: Michael
authors.initials: M
authors.lastname: Rowley
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Summa
mesh_terms: 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