ABSTRACT
The cis-3-amino-4-(2-cyanopyrrolidide)-pyrrolidine template has been shown to afford low nanomolar inhibitors of human DPP-IV that exhibit a robust PK/PD profile. An X-ray co-crystal structure of 5 confirmed the proposed mode of binding. The potent single digit DPP-IV inhibitor 53 exhibited a preferred PK/PD profile in preclinical animal models and was selected for additional profiling.
Subject(s)
Benzene/chemistry , Cyanides/chemistry , Dipeptidyl-Peptidase IV Inhibitors , Protease Inhibitors/chemical synthesis , Protease Inhibitors/pharmacology , Pyrroles/chemistry , Pyrroles/pharmacology , Amination , Animals , Dipeptidyl Peptidase 4/chemistry , Dipeptidyl Peptidase 4/metabolism , Dogs , Drug Design , Humans , Inhibitory Concentration 50 , Models, Molecular , Molecular Structure , Protease Inhibitors/chemistry , Rats , Stereoisomerism , Structure-Activity RelationshipABSTRACT
3-Alkoxymethyl- and 3-aryloxymethyl-2-pyridinones were synthesized and evaluated for activity as non-nucleoside reverse transcriptase inhibitors (NNRTIs) of HIV-1. It was found that several compounds were potent inhibitors of HIV-1 with the most potent compound 24 exhibiting an IC90 = 32 nM. Compound 24 also possessed a potent resistance profile as demonstrated by submicromolar IC90s against several clinically meaningful mutant virus strains.
Subject(s)
Anti-HIV Agents/chemical synthesis , HIV Reverse Transcriptase/antagonists & inhibitors , Pyridones/pharmacology , Anti-HIV Agents/pharmacology , Combinatorial Chemistry Techniques , Cytopathogenic Effect, Viral/drug effects , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/pharmacology , Fluorine/chemistry , HIV Reverse Transcriptase/genetics , HIV-1/drug effects , HIV-1/genetics , Inhibitory Concentration 50 , Mutation , Pyridones/chemical synthesis , Structure-Activity RelationshipABSTRACT
A series of unique 3,3a-dihydropyrano[4,3,2-de]quinazolin-2(1H)-ones and a 2a,5-dihydro-2H-thieno[4,3,2-de]quinazo-line-4(3H)-thione were found to be HIV-1 non-nucleoside reverse transcriptase inhibitors. One of these compounds, as the racemate, possessed an IC90 = 4.6 nM against wild-type virus in a whole cell antiviral assay and had an IC90 = 76 and 897 nM against the clinically significant K103N and K103N/L100I mutant viruses, respectively.
Subject(s)
HIV Reverse Transcriptase/antagonists & inhibitors , Pyrans/pharmacology , Quinazolines/pharmacology , Reverse Transcriptase Inhibitors/chemical synthesis , Binding Sites , Combinatorial Chemistry Techniques , Drug Resistance , HIV Reverse Transcriptase/genetics , Heterocyclic Compounds, 2-Ring/chemical synthesis , Heterocyclic Compounds, 2-Ring/pharmacology , Heterocyclic Compounds, 3-Ring/chemical synthesis , Heterocyclic Compounds, 3-Ring/pharmacology , Humans , Inhibitory Concentration 50 , Models, Molecular , Point Mutation , Pyrans/chemical synthesis , Quinazolines/chemical synthesis , Reverse Transcriptase Inhibitors/pharmacology , Structure-Activity RelationshipABSTRACT
A series of 4-alkenyl and 4-alkynyl-3, 4-dihydro-4-(trifluoromethyl)-2-(1H)-quinazolinones were found to be potent non-nucleoside reverse transcriptase inhibitors (NNRTIs) of human immunodeficiency virus type-1 (HIV-1). The 4-alkenyl-3, 4-dihydro-4-(trifluoromethyl)-2-(1H)-quinazolinones DPC 082 and DPC 083 and the 4-alkynyl-3, 4-dihydro-4-(trifluoromethyl)-2-(1H)-quinazolinones DPC 961 and DPC 963 were found to exhibit low nanomolar potency toward wild-type RF virus (IC(90) = 2.0, 2.1, 2.0, and 1.3 nM, respectively) and various single and many multiple amino acid substituted HIV-1 mutant viruses. The increased potency is combined with favorable plasma serum protein binding as demonstrated by improvements in the percent free drug in human plasma when compared to efavirenz: 3.0%, 2.0%, 1.5%, 2. 8%, and 0.2-0.5% for DPC 082, DPC 083, DPC 961, DPC 963, and efavirenz, respectively.
Subject(s)
Anti-HIV Agents/chemical synthesis , HIV Reverse Transcriptase/antagonists & inhibitors , HIV-1/drug effects , Mutation , Quinazolines/chemical synthesis , Reverse Transcriptase Inhibitors/chemical synthesis , Alkynes , Anti-HIV Agents/blood , Anti-HIV Agents/pharmacology , Benzoxazines , Blood Proteins/metabolism , Cyclopropanes , HIV-1/genetics , Humans , Molecular Structure , Oxazines/blood , Oxazines/pharmacology , Protein Binding , Quinazolines/blood , Quinazolines/pharmacology , Reverse Transcriptase Inhibitors/blood , Reverse Transcriptase Inhibitors/pharmacology , Structure-Activity Relationship , Virus Replication/drug effectsABSTRACT
Benzothiadiazine non-nucleoside reverse transcriptase inhibitors (NNRTIs) of HIV have been synthesized via a novel process to afford active inhibitors, with the most potent compound exhibiting an IC90 = 180 nM in a whole cell assay. The 2,2-dioxide-1H-2,1,3-benzothiadiazine ring system was constructed in one step from 2-amino-5-chlorobenzonitrile.
Subject(s)
Benzothiadiazines/chemical synthesis , Reverse Transcriptase Inhibitors/chemical synthesis , Benzothiadiazines/pharmacology , HIV-1/enzymology , Humans , Molecular Structure , Reverse Transcriptase Inhibitors/pharmacologyABSTRACT
A research program targeted toward the identification of expanded-spectrum nonnucleoside reverse transcriptase inhibitors which possess increased potency toward K103N-containing mutant human immunodeficiency virus (HIV) and which maintain pharmacokinetics consistent with once-a-day dosing has resulted in the identification of the 4-cyclopropylalkynyl-4-trifluoromethyl-3, 4-dihydro-2(1H)quinazolinones DPC 961 and DPC 963 and the 4-cyclopropylalkenyl-4-trifluoromethyl-3, 4-dihydro-2(1H)quinazolinones DPC 082 and DPC 083 for clinical development. DPC 961, DPC 963, DPC 082, and DPC 083 all exhibit low-nanomolar potency toward wild-type virus, K103N and L100I single-mutation variants, and many multiply amino acid-substituted HIV type 1 mutants. This high degree of potency is combined with a high degree of oral bioavailability, as demonstrated in rhesus monkeys and chimpanzees, and with plasma serum protein binding that can result in significant free levels of drug.
Subject(s)
Anti-HIV Agents/pharmacology , HIV Reverse Transcriptase/antagonists & inhibitors , HIV-1/drug effects , HIV-1/genetics , Mutation/physiology , Reverse Transcriptase Inhibitors/pharmacology , Amino Acid Substitution/genetics , Animals , Anti-HIV Agents/pharmacokinetics , Blood Proteins/metabolism , HIV-1/enzymology , Half-Life , Humans , Macaca mulatta , Male , Pan troglodytes , Protein Binding , Reverse Transcriptase Inhibitors/pharmacokinetics , StereoisomerismABSTRACT
[2S*-(2 beta,3 alpha,6 alpha,12b beta)]-Methyl 3-acetyl-1,2,3,4,6,7,12,12b-octahydro-6-methoxycarbonyl-indolo+ ++[2,3-a] quinolizine-3-ethanoate, C22H26N2O5, M(r) = 398.46, orthorhombic, P2(1)2(1)2(1), a = 9.463 (2), b = 11.251 (3), c = 18.871 (6) A, V = 2009.2 (9) A3, Z = 4, Dx = 1.32 g cm-3 (178 K), lambda(Mo K alpha) = 0.7107 A, mu = 0.8762 cm-1, F(000) = 848, T = 178 K, R = 0.0536 for 1673 reflections [Fo > or = 6 sigma (Fo)]. Molecules are hydrogen bonded along the 2(1)-screw axis parallel to a. The hydrogen-bond geometric parameters for N12-H12...O19 (related by 0.5 + x, 1.5 - y, 1 - z) are N...O 2.986 (6), H...O 2.30 (5) A, N-H...O 161 (5) degrees. The C and D rings are trans fused with ring-junction torsion angles of -39.6 (5) and 63.8 (5) degrees for C12a-C12b-N5-C6 and C1-C12b-N5-C4, respectively. The conformation of the C ring is half chair with N5 and C6 -0.168 (4) and 0.552 (5) A, respectively, out of the plane defined by the remaining four atoms of the ring. The D ring is in the chair conformation.
Subject(s)
Secologanin Tryptamine Alkaloids , Yohimbine/analogs & derivatives , Crystallization , Hydrogen Bonding , Molecular Conformation , Molecular Structure , X-Ray Diffraction , Yohimbine/chemical synthesis , Yohimbine/chemistryABSTRACT
Methyl [4aS*-(4 alpha,4a beta,7 beta,13b beta,14a beta)]-7,8,13,13b,14,14a- hexahydro-4-methyl-5-oxo-4H-indolo-[2,3-a]pyrano[3,4-g]qu inolizine-7-carboxylate acetone solvate, C22H22N2O4.C3H6O, Mr = 424.50, triclinic, P1, a = 9.9955(13), b = 10.8523(14), c = 11.9352(14) A, alpha = 63.189(9), beta = 72.286(9), gamma = 72.901(10) degrees, V = 1081.8(2) A3, Z = 2, Dx = 1.30 g cm-3(198K), mu = 0.8554 cm-1, Mo K alpha radiation, lambda = 0.7107 A, F(000) = 452, T = 198 K, R = 0.0435 for 3842 reflections, FO greater than or equal to 4 sigma (FO). The acetone solvent is hydrogen bonded to the indole NH group with relevant parameters: N13...O1A 2.982(2), H13...O1A 2.10(2) A, N--H...O 164(2) degrees. The conformation at the C and D ring junction is quasi-cis [relevant torsion angles are C7--N6--C13B--C13A 9.4(2) degrees and C5--N6--C13B--C14 46.7(2) degrees] while the conformation at the D and E ring junction is cis [relevant torsion angles are 37.8(2) degrees for C5--C4A--C14A--C14 and 41.3(2) degrees for C4--C4A--C14A--C1].
