Structural and Preclinical Studies of Computationally Designed Non-Nucleoside Reverse Transcriptase Inhibitors for Treating HIV infection.
The clinical benefits of HIV-1 non-nucleoside reverse transcriptase (RT) inhibitors (NNRTIs) are hindered by their unsatisfactory pharmacokinetic (PK) properties along with the rapid development of drug-resistant variants. However, the clinical efficacy of these inhibitors can be improved by developing compounds with enhanced pharmacological profiles and heightened antiviral activity. We used computational and structure-guided design to develop two next-generation NNRTI drug candidates, compounds I and II, which are members of a class of catechol diethers. We evaluated the preclinical potential of these compounds in BALB/c mice because of their high solubility (510µg/ml for compound I and 82.9µg/ml for compound II), low cytotoxicity, and enhanced antiviral activity against wild-type (WT) HIV-1 RT and resistant variants. Additionally, crystal structures of compounds I and II with WT RT suggested an optimal binding to the NNRTI binding pocket favoring the high anti-viral potency. A single intraperitoneal dose of compounds I and II exhibited a prolonged serum residence time of 48 hours and concentration maximum (Cmax) of 4000- to 15,000-fold higher than their therapeutic/effective concentrations. TheseCmaxvalues were 4- to 15-fold lower than their cytotoxic concentrations observed in MT-2 cells. Compound II showed an enhanced area under the curve (0-last) and decreased plasma clearance over compound I and efavirenz, the standard of care NNRTI. Hence, the overall (PK) profile of compound II was excellent compared with that of compound I and efavirenz. Furthermore, both compounds were very well tolerated in BALB/c mice without any detectable acute toxicity. Taken together, these data suggest that compounds I and II possess improved anti-HIV-1 potency, remarkable in vivo safety, and prolonged in vivo circulation time, suggesting strong potential for further development as new NNRTIs for the potential treatment of HIV infection.
Departments of Pharmacology, School of Medicine (S.N.K., A.H.C., K.S.A.), Infectious Diseases/Internal Medicine, School of Medicine (J.B., P.K.), and Chemistry (W.-G.L., W.L.J.), Yale University, New Haven, Connecticut.
Shalley N
SN
Kudalkar
Departments of Pharmacology, School of Medicine (S.N.K., A.H.C., K.S.A.), Infectious Diseases/Internal Medicine, School of Medicine (J.B., P.K.), and Chemistry (W.-G.L., W.L.J.), Yale University, New Haven, Connecticut.
Jagadish
J
Beloor
Departments of Pharmacology, School of Medicine (S.N.K., A.H.C., K.S.A.), Infectious Diseases/Internal Medicine, School of Medicine (J.B., P.K.), and Chemistry (W.-G.L., W.L.J.), Yale University, New Haven, Connecticut.
Albert H
AH
Chan
Departments of Pharmacology, School of Medicine (S.N.K., A.H.C., K.S.A.), Infectious Diseases/Internal Medicine, School of Medicine (J.B., P.K.), and Chemistry (W.-G.L., W.L.J.), Yale University, New Haven, Connecticut.
Won-Gil
WG
Lee
Departments of Pharmacology, School of Medicine (S.N.K., A.H.C., K.S.A.), Infectious Diseases/Internal Medicine, School of Medicine (J.B., P.K.), and Chemistry (W.-G.L., W.L.J.), Yale University, New Haven, Connecticut.
William L
WL
Jorgensen
Departments of Pharmacology, School of Medicine (S.N.K., A.H.C., K.S.A.), Infectious Diseases/Internal Medicine, School of Medicine (J.B., P.K.), and Chemistry (W.-G.L., W.L.J.), Yale University, New Haven, Connecticut karen.anderson@yale.edu priti.kumar@yale.edu.
Priti
P
Kumar
Departments of Pharmacology, School of Medicine (S.N.K., A.H.C., K.S.A.), Infectious Diseases/Internal Medicine, School of Medicine (J.B., P.K.), and Chemistry (W.-G.L., W.L.J.), Yale University, New Haven, Connecticut karen.anderson@yale.edu priti.kumar@yale.edu.
Karen S
KS
Anderson
D000480:Alkynes; D000818:Animals; D048588:Benzoxazines / Q000737:chemistry / Q000494:pharmacology; D018360:Crystallography, X-Ray; D003521:Cyclopropanes; D015195:Drug Design; D004353:Drug Evaluation, Preclinical; D005260:Female; D015658:HIV Infections / Q000188:drug therapy* / Q000821:virology; D015497:HIV-1 / Q000187:drug effects; D006801:Humans; D020128:Inhibitory Concentration 50; D008807:Mice, Inbred BALB C; D018894:Reverse Transcriptase Inhibitors / Q000737:chemistry* / Q000493:pharmacokinetics / Q000627:therapeutic use* / Q000633:toxicity; D012995:Solubility
D000480:Alkynes; D048588:Benzoxazines; D003521:Cyclopropanes; D018894:Reverse Transcriptase Inhibitors; C098320:efavirenz