title: Design and synthesis of conformationally constrained inhibitors of non-nucleoside reverse transcriptase.
abstract: Highly active antiretroviral therapy (HAART) significantly reduces human immunodeficiency virus (HIV) viral load and has led to a dramatic decrease in acquired immunodeficiency syndrome (AIDS) related mortality. Despite this success,  there remains a critical need for new HIV therapies to address the emergence of drug resistant viral strains. Next generation NNRTIs are sought that are effective against these mutant forms of the HIV virus. The bound conformations of our lead inhibitors, MK-1107 (1) and MK-4965 (2), were divergent about the oxymethylene linker, and each of these conformations was rigidified using two isomeric cyclic constraints. The constraint derived from the bioactive conformation of 2provided novel, highly potent NNRTIs that possess broad spectrum antiviral activity and good pharmacokinetic profiles. Systematic SAR led to the identification of indazole as the optimal conformational constraint to provide MK-6186 (3) and MK-7445 (6). Despite their reduced flexibility, these compounds had potency comparable to that of the corresponding acyclic ethers in both recombinant enzyme and cell based assays against both the wild-type and the clinically relevant mutant strains.
authors: Departments of West Point Discovery Chemistry, Pennsylvania 19486-0004, United States. Robert_gomez@merck.com
authors: Robert
authors: R
authors: Gomez
authors: Samson J
authors: SJ
authors: Jolly
authors: Theresa
authors: T
authors: Williams
authors: Joseph P
authors: JP
authors: Vacca
authors: Maricel
authors: M
authors: Torrent
authors: Georgia
authors: G
authors: McGaughey
authors: Ming-Tain
authors: MT
authors: Lai
authors: Peter
authors: P
authors: Felock
authors: Vandna
authors: V
authors: Munshi
authors: Daniel
authors: D
authors: Distefano
authors: Jessica
authors: J
authors: Flynn
authors: Mike
authors: M
authors: Miller
authors: Youwei
authors: Y
authors: Yan
authors: John
authors: J
authors: Reid
authors: Rosa
authors: R
authors: Sanchez
authors: Yuexia
authors: Y
authors: Liang
authors: Brenda
authors: B
authors: Paton
authors: Bang-Lin
authors: BL
authors: Wan
authors: Neville
authors: N
authors: Anthony
mesh_terms: D000818:Animals; D019380:Anti-HIV Agents / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D002478:Cells, Cultured; D004285:Dogs; D054303:HIV Reverse Transcriptase / Q000737:chemistry / Q000378:metabolism; D015497:HIV-1 / Q000187:drug effects / Q000235:genetics / Q000302:isolation & purification; D006801:Humans; D007093:Imidazoles / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D007191:Indazoles / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D008958:Models, Molecular; D008968:Molecular Conformation; D009154:Mutation; D009570:Nitriles / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000494:pharmacology; D009578:Nitrobenzenes / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000494:pharmacology; D011720:Pyrazoles / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D011994:Recombinant Proteins / Q000737:chemistry; D018894:Reverse Transcriptase Inhibitors / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D013329:Structure-Activity Relationship; D013816:Thermodynamics; D014230:Triazoles / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology
chemical_list: D019380:Anti-HIV Agents; D007093:Imidazoles; D007191:Indazoles; D009570:Nitriles; D009578:Nitrobenzenes; D011720:Pyrazoles; D011994:Recombinant Proteins; D018894:Reverse Transcriptase Inhibitors; D014230:Triazoles; D054303:HIV Reverse Transcriptase