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1.
J Med Chem ; 66(23): 15629-15647, 2023 12 14.
Article in English | MEDLINE | ID: mdl-37967851

ABSTRACT

Transcriptional deregulation is a hallmark of many cancers and is exemplified by genomic amplifications of the MYC family of oncogenes, which occur in at least 20% of all solid tumors in adults. Targeting of transcriptional cofactors and the transcriptional cyclin-dependent kinase (CDK9) has emerged as a therapeutic strategy to interdict deregulated transcriptional activity including oncogenic MYC. Here, we report the structural optimization of a small molecule microarray hit, prioritizing maintenance of CDK9 selectivity while improving on-target potency and overall physicochemical and pharmacokinetic (PK) properties. This led to the discovery of the potent, selective, orally bioavailable CDK9 inhibitor 28 (KB-0742). Compound 28 exhibits in vivo antitumor activity in mouse xenograft models and a projected human PK profile anticipated to enable efficacious oral dosing. Notably, 28 is currently being investigated in a phase 1/2 dose escalation and expansion clinical trial in patients with relapsed or refractory solid tumors.


Subject(s)
Antineoplastic Agents , Neoplasms , Adult , Humans , Animals , Mice , Cyclin-Dependent Kinases , Cell Line, Tumor , Antineoplastic Agents/pharmacology , Antineoplastic Agents/therapeutic use , Antineoplastic Agents/chemistry , Apoptosis , Cell Cycle Checkpoints , Disease Models, Animal , Protein Kinase Inhibitors/pharmacology , Protein Kinase Inhibitors/therapeutic use , Protein Kinase Inhibitors/chemistry , Cyclin-Dependent Kinase 9 , Neoplasms/drug therapy
2.
ACS Chem Neurosci ; 13(13): 1849-1856, 2022 07 06.
Article in English | MEDLINE | ID: mdl-35738565

ABSTRACT

The kappa agonist structure-activity relationship around the novel, pyrrolidinyl substituted pyranopiperazine scaffold was developed. More specifically, the dichloroPhenylAcetamide-Pyrrolidinyl-PyranoPiperazine (PAPPP) core A was the focus of our work. The modulation of kappa receptor potency/G-protein activation and arrestin recruitment with respect to changes of the piperazine R group in A was demonstrated. Reduced ß2-arrestin recruitment and differential G-protein bias were observed for select analogues. To better understand the subtlety in receptor signaling, analogues were profiled as the resolved enantiomers. To determine in vivo target engagement, a subset of compounds was tested in mice for stimulation of serum prolactin, a neuroendocrine biomarker of KOR-agonist effects. Additional in vivo characterization included measurement of potential unwanted effects of kappa receptor activation such as sedation. These studies demonstrate a novel kappa receptor agonist scaffold with potential for G-protein signaling bias to probe in vivo pharmacology.


Subject(s)
Analgesics, Opioid , Receptors, Opioid, kappa , Analgesics, Opioid/pharmacology , Animals , Arrestins/metabolism , GTP-Binding Proteins/metabolism , Mice , Receptors, Opioid, kappa/metabolism , Signal Transduction
3.
Cell Chem Biol ; 28(2): 134-147.e14, 2021 02 18.
Article in English | MEDLINE | ID: mdl-33086052

ABSTRACT

Castration-resistant prostate cancers (CRPCs) lose sensitivity to androgen-deprivation therapies but frequently remain dependent on oncogenic transcription driven by the androgen receptor (AR) and its splice variants. To discover modulators of AR-variant activity, we used a lysate-based small-molecule microarray assay and identified KI-ARv-03 as an AR-variant complex binder that reduces AR-driven transcription and proliferation in prostate cancer cells. We deduced KI-ARv-03 to be a potent, selective inhibitor of CDK9, an important cofactor for AR, MYC, and other oncogenic transcription factors. Further optimization resulted in KB-0742, an orally bioavailable, selective CDK9 inhibitor with potent anti-tumor activity in CRPC models. In 22Rv1 cells, KB-0742 rapidly downregulates nascent transcription, preferentially depleting short half-life transcripts and AR-driven oncogenic programs. In vivo, oral administration of KB-0742 significantly reduced tumor growth in CRPC, supporting CDK9 inhibition as a promising therapeutic strategy to target AR dependence in CRPC.


Subject(s)
Androgen Receptor Antagonists/pharmacology , Cyclin-Dependent Kinase 9/antagonists & inhibitors , Prostatic Neoplasms, Castration-Resistant/drug therapy , Protein Kinase Inhibitors/pharmacology , Receptors, Androgen/genetics , Transcription, Genetic/drug effects , Androgen Receptor Antagonists/therapeutic use , Animals , Cell Line, Tumor , Cyclin-Dependent Kinase 9/genetics , Gene Expression Regulation, Neoplastic/drug effects , Male , Mice , Mice, Inbred BALB C , Models, Molecular , Prostatic Neoplasms, Castration-Resistant/genetics , Protein Kinase Inhibitors/therapeutic use
4.
Cell ; 175(1): 171-185.e25, 2018 09 20.
Article in English | MEDLINE | ID: mdl-30146162

ABSTRACT

CKIα ablation induces p53 activation, and CKIα degradation underlies the therapeutic effect of lenalidomide in a pre-leukemia syndrome. Here we describe the development of CKIα inhibitors, which co-target the transcriptional kinases CDK7 and CDK9, thereby augmenting CKIα-induced p53 activation and its anti-leukemic activity. Oncogene-driving super-enhancers (SEs) are highly sensitive to CDK7/9 inhibition. We identified multiple newly gained SEs in primary mouse acute myeloid leukemia (AML) cells and demonstrate that the inhibitors abolish many SEs and preferentially suppress the transcription elongation of SE-driven oncogenes. We show that blocking CKIα together with CDK7 and/or CDK9 synergistically stabilize p53, deprive leukemia cells of survival and proliferation-maintaining SE-driven oncogenes, and induce apoptosis. Leukemia progenitors are selectively eliminated by the inhibitors, explaining their therapeutic efficacy with preserved hematopoiesis and leukemia cure potential; they eradicate leukemia in MLL-AF9 and Tet2-/-;Flt3ITD AML mouse models and in several patient-derived AML xenograft models, supporting their potential efficacy in curing human leukemia.


Subject(s)
Casein Kinase Ialpha/antagonists & inhibitors , Leukemia, Myeloid, Acute/drug therapy , Animals , Apoptosis/drug effects , Casein Kinase Ialpha/physiology , Cell Proliferation/drug effects , Cyclin-Dependent Kinase 9/antagonists & inhibitors , Cyclin-Dependent Kinase 9/physiology , Cyclin-Dependent Kinases/antagonists & inhibitors , Cyclin-Dependent Kinases/physiology , DNA-Binding Proteins , Disease Models, Animal , Enhancer Elements, Genetic/genetics , Hematopoiesis , Humans , Mice , Mice, Inbred C57BL , Oncogene Proteins, Fusion/metabolism , Protein Serine-Threonine Kinases , Proto-Oncogene Proteins , Tumor Suppressor Protein p53/physiology , Xenograft Model Antitumor Assays
5.
ACS Infect Dis ; 3(5): 349-359, 2017 05 12.
Article in English | MEDLINE | ID: mdl-28215073

ABSTRACT

In 2013, the Centers for Disease Control highlighted Clostridium difficile as an urgent threat for antibiotic-resistant infections, in part due to the emergence of highly virulent fluoroquinolone-resistant strains. Limited therapeutic options currently exist, many of which result in disease relapse. We sought to identify molecules specifically targeting C. difficile in high-throughput screens of our diversity-oriented synthesis compound collection. We identified two scaffolds with apparently novel mechanisms of action that selectively target C. difficile while having little to no activity against other intestinal anaerobes; preliminary evidence suggests that compounds from one of these scaffolds target the glutamate racemase. In vivo efficacy data suggest that both compound series may provide lead optimization candidates.


Subject(s)
Amino Acid Isomerases/antagonists & inhibitors , Anti-Bacterial Agents/pharmacology , Bacterial Proteins/antagonists & inhibitors , Clostridioides difficile/drug effects , Enterocolitis, Pseudomembranous/drug therapy , Heterocyclic Compounds, 2-Ring/pharmacology , Phenylurea Compounds/pharmacology , Pyrroles/pharmacology , Quinolines/pharmacology , Amino Acid Isomerases/genetics , Amino Acid Isomerases/metabolism , Animals , Anti-Bacterial Agents/chemical synthesis , Bacterial Proteins/genetics , Bacterial Proteins/metabolism , Clostridioides difficile/enzymology , Clostridioides difficile/genetics , Clostridioides difficile/growth & development , Drug Design , Enterocolitis, Pseudomembranous/microbiology , Enterocolitis, Pseudomembranous/mortality , Enterocolitis, Pseudomembranous/pathology , Female , Gene Expression , Gram-Negative Bacteria/drug effects , Gram-Negative Bacteria/growth & development , Gram-Positive Bacteria/drug effects , Gram-Positive Bacteria/growth & development , Heterocyclic Compounds, 2-Ring/chemical synthesis , Mice , Mice, Inbred C57BL , Microbial Sensitivity Tests , Phenylurea Compounds/chemical synthesis , Pyrroles/chemical synthesis , Quinolines/chemical synthesis , Species Specificity , Structure-Activity Relationship , Survival Analysis
6.
ACS Med Chem Lett ; 7(7): 702-7, 2016 Jul 14.
Article in English | MEDLINE | ID: mdl-27437081

ABSTRACT

A novel HIV protease inhibitor was designed using a morpholine core as the aspartate binding group. Analysis of the crystal structure of the initial lead bound to HIV protease enabled optimization of enzyme potency and antiviral activity. This afforded a series of potent orally bioavailable inhibitors of which MK-8718 was identified as a compound with a favorable overall profile.

7.
Bioorg Med Chem Lett ; 25(21): 4812-4819, 2015 Nov 01.
Article in English | MEDLINE | ID: mdl-26195137

ABSTRACT

The IC50 of a beta-secretase (BACE-1) lead compound was improved ∼200-fold from 11 µM to 55 nM through the addition of a single methyl group. Computational chemistry, small molecule NMR, and protein crystallography capabilities were used to compare the solution conformation of the ligand under varying pH conditions to its conformation when bound in the active site. Chemical modification then explored available binding pockets adjacent to the ligand. A strategically placed methyl group not only maintained the required pKa of the piperidine nitrogen and filled a small hydrophobic pocket, but more importantly, stabilized the conformation best suited for optimized binding to the receptor.


Subject(s)
Amyloid Precursor Protein Secretases/antagonists & inhibitors , Aspartic Acid Endopeptidases/antagonists & inhibitors , Hydantoins/chemistry , Hydantoins/pharmacology , Amyloid Precursor Protein Secretases/metabolism , Aspartic Acid Endopeptidases/metabolism , Crystallography, X-Ray , Dose-Response Relationship, Drug , Humans , Hydantoins/chemical synthesis , Methylation , Models, Molecular , Molecular Structure , Structure-Activity Relationship
8.
ACS Med Chem Lett ; 5(3): 264-9, 2014 Mar 13.
Article in English | MEDLINE | ID: mdl-24900818

ABSTRACT

We have previously reported the discovery of our P2-P4 macrocyclic HCV NS3/4a protease inhibitor MK-5172, which in combination with the NS5a inhibitor MK-8742 recently received a breakthrough therapy designation from the US FDA for treatment of chronic HCV infection. Our goal for the next generation NS3/4a inhibitor was to achieve pan-genotypic activity while retaining the pharmacokinetic profile of MK-5172. One of the areas for follow-up investigation involved replacement of the quinoxaline moiety in MK-5172 with a quinoline and studying the effect of substitution at 4-position of the quinoline. The rationale for this effort was based on molecular modeling, which indicated that such modifications would improve interactions with the S2 subsite, in particular with D79. We wish to report herein the discovery of highly potent inhibitors with pan-genotypic activity and an improved profile over MK-5172, especially against gt-3a and A156 mutants.

9.
J Org Chem ; 78(23): 12029-39, 2013 Dec 06.
Article in English | MEDLINE | ID: mdl-24224609

ABSTRACT

Formylthiocholine (FTC) was synthesized and found to be a substrate for nonenzymatic and butyrylcholinesterase (BChE)-catalyzed hydrolysis. Solvent (D2O) and secondary formyl-H kinetic isotope effects (KIEs) were measured by an NMR spectroscopic method. The solvent (D2O) KIEs are (D2O)k = 0.20 in 200 mM HCl, (D2O)k = 0.81 in 50 mM HCl, and (D2O)k = 4.2 in pure water. The formyl-H KIEs are (D)k = 0.80 in 200 mM HCl, (D)k = 0.77 in 50 mM HCl, (D)k = 0.75 in pure water, (D)k = 0.88 in 50 mM NaOH, and (D)(V/K) = 0.89 in the BChE-catalyzed hydrolysis in MES buffer at pH 6.8. Positional isotope exchange experiments showed no detectable exchange of (18)O into the carbonyl oxygen of FTC or the product, formate, under any of the above conditions. Solvent nucleophile-O KIEs were determined to be (18)k = 0.9917 under neutral conditions, (18)k = 1.0290 (water nucleophile) or (18)k = 0.989 (hydroxide nucleophile) under alkaline conditions, and (18)(V/K) = 0.9925 for BChE catalysis. The acidic, neutral, and BChE-catalyzed reactions are explained in terms of a stepwise mechanism with tetrahedral intermediates. Evidence for a change to a direct displacement mechanism under alkaline conditions is presented.


Subject(s)
Butyrylcholinesterase/metabolism , Deuterium Oxide/chemistry , Esters/metabolism , Sulfhydryl Compounds/metabolism , Biocatalysis , Butyrylcholinesterase/blood , Esters/chemistry , Kinetics , Molecular Structure , Oxygen Isotopes , Sulfhydryl Compounds/chemistry
10.
ChemMedChem ; 8(12): 1930-40, 2013 Dec.
Article in English | MEDLINE | ID: mdl-24127258

ABSTRACT

The NS5A protein plays a critical role in the replication of HCV and has been the focus of numerous research efforts over the past few years. NS5A inhibitors have shown impressive in vitro potency profiles in HCV replicon assays, making them attractive components for inclusion in all oral combination regimens. Early work in the NS5A arena led to the discovery of our first clinical candidate, MK-4882 [2-((S)-pyrrolidin-2-yl)-5-(2-(4-(5-((S)-pyrrolidin-2-yl)-1H-imidazol-2-yl)phenyl)benzofuran-5-yl)-1H-imidazole]. While preclinical proof-of-concept studies in HCV-infected chimpanzees harboring chronic genotype 1 infections resulted in significant decreases in viral load after both single- and multiple-dose treatments, viral breakthrough proved to be a concern, thus necessitating the development of compounds with increased potency against a number of genotypes and NS5A resistance mutations. Modification of the MK-4882 core scaffold by introduction of a cyclic constraint afforded a series of tetracyclic inhibitors, which showed improved virologic profiles. Herein we describe the research efforts that led to the discovery of MK-8742, a tetracyclic indole-based NS5A inhibitor, which is currently in phase 2b clinical trials as part of an all-oral, interferon-free regimen for the treatment of HCV infection.


Subject(s)
Antiviral Agents/chemistry , Benzofurans/chemistry , Enzyme Inhibitors/chemistry , Hepacivirus/enzymology , Imidazoles/chemistry , Viral Nonstructural Proteins/antagonists & inhibitors , Animals , Antiviral Agents/chemical synthesis , Antiviral Agents/pharmacokinetics , Benzofurans/chemical synthesis , Benzofurans/pharmacokinetics , Dogs , Drug Evaluation, Preclinical , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/pharmacokinetics , Half-Life , Hepacivirus/drug effects , Hepacivirus/genetics , Imidazoles/chemical synthesis , Imidazoles/pharmacokinetics , Indoles/chemistry , Mutation , Pan troglodytes , Protein Binding , Rats , Structure-Activity Relationship , Viral Nonstructural Proteins/genetics , Viral Nonstructural Proteins/metabolism
11.
Bioorg Med Chem Lett ; 22(23): 7207-13, 2012 Dec 01.
Article in English | MEDLINE | ID: mdl-23084906

ABSTRACT

A series of macrocyclic compounds containing a cyclic constraint in the P2-P4 linker region have been discovered and shown to exhibit excellent HCV NS3/4a genotype 3a and genotype 1b R155K, A156T, A156V, and D168V mutant activity while maintaining high rat liver exposure. The effect of the constraint is most dramatic against gt 1b A156 mutants where ~20-fold improvements in potency are achieved by introduction of a variety of ring systems into the P2-P4 linker.


Subject(s)
Carrier Proteins/antagonists & inhibitors , Hepacivirus/enzymology , Macrocyclic Compounds/chemistry , Protease Inhibitors/chemistry , Viral Nonstructural Proteins/antagonists & inhibitors , Animals , Binding Sites , Carrier Proteins/metabolism , Catalytic Domain , Cyclization , Genotype , Half-Life , Hepacivirus/genetics , Intracellular Signaling Peptides and Proteins , Kinetics , Liver/metabolism , Macrocyclic Compounds/chemical synthesis , Macrocyclic Compounds/pharmacokinetics , Molecular Docking Simulation , Mutation , Protease Inhibitors/chemical synthesis , Protease Inhibitors/pharmacokinetics , Rats , Structure-Activity Relationship , Viral Nonstructural Proteins/metabolism
12.
Bioorg Med Chem Lett ; 22(23): 7201-6, 2012 Dec 01.
Article in English | MEDLINE | ID: mdl-23021993

ABSTRACT

A series of macrocyclic compounds containing 2-substituted-quinoline moieties have been discovered and shown to exhibit excellent HCV NS3/4a genotype 3a and genotype 1b R155K mutant activity while maintaining the high rat liver exposure. Cyclization of the 2-substituted quinoline substituent led to a series of tricyclic P2 compounds which also display superb gt3a potency.


Subject(s)
Carrier Proteins/antagonists & inhibitors , Hepacivirus/enzymology , Macrocyclic Compounds/chemistry , Protease Inhibitors/chemistry , Viral Nonstructural Proteins/antagonists & inhibitors , Animals , Carrier Proteins/metabolism , Cyclization , Genotype , Half-Life , Hepacivirus/genetics , Intracellular Signaling Peptides and Proteins , Kinetics , Liver/metabolism , Macrocyclic Compounds/chemical synthesis , Macrocyclic Compounds/pharmacokinetics , Protease Inhibitors/chemical synthesis , Protease Inhibitors/pharmacokinetics , Quinolines/chemistry , Rats , Structure-Activity Relationship , Viral Nonstructural Proteins/metabolism
13.
Bioorg Med Chem Lett ; 22(13): 4341-7, 2012 Jul 01.
Article in English | MEDLINE | ID: mdl-22658862

ABSTRACT

Long chain L-2-hydroxy acid oxidase 2 (Hao2) is a peroxisomal enzyme expressed in the kidney and the liver. Hao2 was identified as a candidate gene for blood pressure (BP) quantitative trait locus (QTL) but the identity of its physiological substrate and its role in vivo remains largely unknown. To define a pharmacological role of this gene product, we report the development of selective inhibitors of Hao2. We identified pyrazole carboxylic acid hits 1 and 2 from screening of a compound library. Lead optimization of these hits led to the discovery of 15-XV and 15-XXXII as potent and selective inhibitors of rat Hao2. This report details the structure activity relationship of the pyrazole carboxylic acids as specific inhibitors of Hao2.


Subject(s)
Alcohol Oxidoreductases/antagonists & inhibitors , Carboxylic Acids/chemistry , Enzyme Inhibitors/chemistry , Pyrazoles/chemistry , Thiophenes/chemistry , Alcohol Oxidoreductases/metabolism , Animals , Binding Sites , Carboxylic Acids/chemical synthesis , Carboxylic Acids/pharmacokinetics , Computer Simulation , Drug Evaluation, Preclinical , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/pharmacokinetics , Humans , Kidney/enzymology , Kidney/metabolism , Liver/enzymology , Liver/metabolism , Protein Structure, Tertiary , Pyrazoles/chemical synthesis , Pyrazoles/therapeutic use , Rats , Structure-Activity Relationship , Thiophenes/chemical synthesis , Thiophenes/therapeutic use
14.
Antimicrob Agents Chemother ; 56(8): 4161-7, 2012 Aug.
Article in English | MEDLINE | ID: mdl-22615282

ABSTRACT

HCV NS3/4a protease inhibitors are proven therapeutic agents against chronic hepatitis C virus infection, with boceprevir and telaprevir having recently received regulatory approval as add-on therapy to pegylated interferon/ribavirin for patients harboring genotype 1 infections. Overcoming antiviral resistance, broad genotype coverage, and a convenient dosing regimen are important attributes for future agents to be used in combinations without interferon. In this communication, we report the preclinical profile of MK-5172, a novel P2-P4 quinoxaline macrocyclic NS3/4a protease inhibitor currently in clinical development. The compound demonstrates subnanomolar activity against a broad enzyme panel encompassing major hepatitis C virus (HCV) genotypes as well as variants resistant to earlier protease inhibitors. In replicon selections, MK-5172 exerted high selective pressure, which yielded few resistant colonies. In both rat and dog, MK-5172 demonstrates good plasma and liver exposures, with 24-h liver levels suggestive of once-daily dosing. When administered to HCV-infected chimpanzees harboring chronic gt1a or gt1b infections, MK-5172 suppressed viral load between 4 to 5 logs at a dose of 1 mg/kg of body weight twice daily (b.i.d.) for 7 days. Based on its preclinical profile, MK-5172 is anticipated to be broadly active against multiple HCV genotypes and clinically important resistance variants and highly suited for incorporation into newer all-oral regimens.


Subject(s)
Hepacivirus/drug effects , Protease Inhibitors/pharmacology , Quinoxalines/pharmacology , Quinoxalines/pharmacokinetics , Viral Nonstructural Proteins/antagonists & inhibitors , Amides , Animals , Antiviral Agents/pharmacology , Carbamates , Cyclopropanes , Dogs , Drug Resistance, Viral , Genotype , Hepacivirus/enzymology , Hepacivirus/genetics , Hepatitis C, Chronic/drug therapy , Hepatitis C, Chronic/virology , Liver/drug effects , Pan troglodytes , Quinoxalines/metabolism , Rats , Sulfonamides , Viral Load/drug effects
15.
Bioorg Med Chem Lett ; 22(12): 3941-5, 2012 Jun 15.
Article in English | MEDLINE | ID: mdl-22607672

ABSTRACT

Rational modification of the clinically tested CGRP receptor antagonist MK-3207 (3) afforded an analogue with increased unbound fraction in rat plasma and enhanced aqueous solubility, 2-[(8R)-8-(3,5-difluorophenyl)-8-methyl-10-oxo-6,9-diazaspiro[4.5]dec-9-yl]-N-[(6S)-2'-oxo-1',2',5,7-tetrahydrospiro[cyclopenta[b]pyridine-6,3'-pyrrolo[2,3-b]pyridin]-3-yl]acetamide (MK-8825) (6). Compound 6 maintained similar affinity to 3 at the human and rat CGRP receptors but possessed significantly improved in vivo potency in a rat pharmacodynamic model. The overall profile of 6 indicates it should find utility as a rat tool to investigate effects of CGRP receptor blockade in vivo.


Subject(s)
Analgesics/chemical synthesis , Analgesics/pharmacology , Calcitonin Gene-Related Peptide Receptor Antagonists , Migraine Disorders/drug therapy , Pyridines/chemical synthesis , Pyridines/pharmacology , Spiro Compounds/chemical synthesis , Spiro Compounds/pharmacology , Administration, Oral , Analgesics/blood , Animals , Biological Availability , Disease Models, Animal , Dogs , Humans , Macaca mulatta , Mice , Pyridines/blood , Rats , Receptors, Calcitonin Gene-Related Peptide/metabolism , Species Specificity , Spiro Compounds/blood
16.
ACS Med Chem Lett ; 3(11): 861, 2012 Nov 08.
Article in English | MEDLINE | ID: mdl-24900391
17.
ACS Med Chem Lett ; 3(4): 332-6, 2012 Apr 12.
Article in English | MEDLINE | ID: mdl-24900473

ABSTRACT

A new class of HCV NS3/4a protease inhibitors containing a P2 to P4 macrocyclic constraint was designed using a molecular modeling-derived strategy. Building on the profile of previous clinical compounds and exploring the P2 and linker regions of the series allowed for optimization of broad genotype and mutant enzyme potency, cellular activity, and rat liver exposure following oral dosing. These studies led to the identification of clinical candidate 15 (MK-5172), which is active against genotype 1-3 NS3/4a and clinically relevant mutant enzymes and has good plasma exposure and excellent liver exposure in multiple species.

18.
Bioorg Med Chem Lett ; 22(1): 240-4, 2012 Jan 01.
Article in English | MEDLINE | ID: mdl-22130130

ABSTRACT

We have developed a novel series of pyrrolidine derived BACE-1 inhibitors. The potency of the weak initial lead structure was enhanced using library-based SAR methods. The series was then further advanced by rational design while maintaining a minimal ligand binding efficiency threshold. Ultimately, the co-crystal structure was obtained revealing that these inhibitors interacted with the enzyme in a unique fashion. In all, the potency of the series was enhanced by 4 orders of magnitude from the HTS lead with concomitant increases in physical properties needed for series advancement. The progression of these developments in a systematic fashion is described.


Subject(s)
Amyloid Precursor Protein Secretases/metabolism , Chemistry, Pharmaceutical/methods , Pyrrolidines/pharmacology , Amyloid Precursor Protein Secretases/antagonists & inhibitors , Aspartic Acid Endopeptidases/antagonists & inhibitors , Crystallization , Crystallography, X-Ray/methods , Drug Design , Enzyme Inhibitors/pharmacology , Inhibitory Concentration 50 , Ligands , Models, Chemical , Protein Binding , Structure-Activity Relationship
19.
J Med Chem ; 54(22): 7920-33, 2011 Nov 24.
Article in English | MEDLINE | ID: mdl-21985673

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.


Subject(s)
Anti-HIV Agents/chemical synthesis , Imidazoles/chemical synthesis , Indazoles/chemical synthesis , Pyrazoles/chemical synthesis , Reverse Transcriptase Inhibitors/chemical synthesis , Triazoles/chemical synthesis , Animals , Anti-HIV Agents/pharmacokinetics , Anti-HIV Agents/pharmacology , Cells, Cultured , Dogs , HIV Reverse Transcriptase/chemistry , HIV Reverse Transcriptase/metabolism , HIV-1/drug effects , HIV-1/genetics , HIV-1/isolation & purification , Humans , Imidazoles/pharmacokinetics , Imidazoles/pharmacology , Indazoles/pharmacokinetics , Indazoles/pharmacology , Models, Molecular , Molecular Conformation , Mutation , Nitriles/chemical synthesis , Nitriles/pharmacokinetics , Nitriles/pharmacology , Nitrobenzenes/chemical synthesis , Nitrobenzenes/pharmacokinetics , Nitrobenzenes/pharmacology , Pyrazoles/pharmacokinetics , Pyrazoles/pharmacology , Rats , Rats, Sprague-Dawley , Recombinant Proteins/chemistry , Reverse Transcriptase Inhibitors/pharmacokinetics , Reverse Transcriptase Inhibitors/pharmacology , Structure-Activity Relationship , Thermodynamics , Triazoles/pharmacokinetics , Triazoles/pharmacology
20.
Bioorg Med Chem Lett ; 21(22): 6705-8, 2011 Nov 15.
Article in English | MEDLINE | ID: mdl-21982500

ABSTRACT

Identification of an HIV integrase inhibitor with micromolar affinity for the CGRP receptor led to the discovery of a series of structurally novel CGRP receptor antagonists. Optimization of this series produced compound 16, a low-molecular weight CGRP receptor antagonist with good pharmacokinetic properties in both rat and dog. In contrast to other nonpeptide antagonists, the activity of 16 was affected by the presence of divalent cations and showed evidence of an alternative, RAMP-independent CGRP receptor binding site.


Subject(s)
Calcitonin Gene-Related Peptide Receptor Antagonists , HIV Integrase Inhibitors/chemistry , HIV Integrase Inhibitors/pharmacology , Pyridines/chemistry , Pyridines/pharmacology , Receptor Activity-Modifying Proteins/metabolism , Receptors, Calcitonin Gene-Related Peptide/metabolism , Animals , Cell Line , Dogs , HIV/enzymology , HIV Integrase Inhibitors/pharmacokinetics , Humans , Protein Binding , Pyridines/pharmacokinetics , Rats
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