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1.
Cancer Discov ; 12(6): 1500-1517, 2022 06 02.
Article in English | MEDLINE | ID: mdl-35404998

ABSTRACT

Covalent inhibitors of KRASG12C have shown antitumor activity against advanced/metastatic KRASG12C-mutated cancers, though resistance emerges and additional strategies are needed to improve outcomes. JDQ443 is a structurally unique covalent inhibitor of GDP-bound KRASG12C that forms novel interactions with the switch II pocket. JDQ443 potently inhibits KRASG12C-driven cellular signaling and demonstrates selective antiproliferative activity in KRASG12C-mutated cell lines, including those with G12C/H95 double mutations. In vivo, JDQ443 induces AUC exposure-driven antitumor efficacy in KRASG12C-mutated cell-derived (CDX) and patient-derived (PDX) tumor xenografts. In PDX models, single-agent JDQ443 activity is enhanced by combination with inhibitors of SHP2, MEK, or CDK4/6. Notably, the benefit of JDQ443 plus the SHP2 inhibitor TNO155 is maintained at reduced doses of either agent in CDX models, consistent with mechanistic synergy. JDQ443 is in clinical development as monotherapy and in combination with TNO155, with both strategies showing antitumor activity in patients with KRASG12C-mutated tumors. SIGNIFICANCE: JDQ443 is a structurally novel covalent KRASG12C inhibitor with a unique binding mode that demonstrates potent and selective antitumor activity in cell lines and in vivo models. In preclinical models and patients with KRASG12C-mutated malignancies, JDQ443 shows potent antitumor activity as monotherapy and in combination with the SHP2 inhibitor TNO155. This article is highlighted in the In This Issue feature, p. 1397.


Subject(s)
Enzyme Inhibitors , Indazoles , Neoplasms , Proto-Oncogene Proteins p21(ras) , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/pharmacology , Humans , Indazoles/chemistry , Indazoles/pharmacology , Mutation , Neoplasms/drug therapy , Neoplasms/enzymology , Neoplasms/genetics , Proto-Oncogene Proteins p21(ras)/antagonists & inhibitors , Proto-Oncogene Proteins p21(ras)/genetics , Proto-Oncogene Proteins p21(ras)/metabolism
2.
J Med Chem ; 58(17): 6747-52, 2015 Sep 10.
Article in English | MEDLINE | ID: mdl-26288344

ABSTRACT

Herein we describe the optimization of a series of PDE4 inhibitors, with special focus on solubility and pharamcokinetics, to clinical compound 2, 4-(8-(3-fluorophenyl)-1,7-naphthyridin-6-yl)transcyclohexanecarboxylic acid. Although compound 2 produces emesis in humans when given as a single dose, its exemplary pharmacokinetic properties enabled a novel dosing regime comprising multiple escalating doses and the resultant achievement of high plasma drug levels without associated nausea or emesis.


Subject(s)
Cyclohexanecarboxylic Acids/chemistry , Naphthyridines/chemistry , Phosphodiesterase 4 Inhibitors/chemistry , Pulmonary Disease, Chronic Obstructive/drug therapy , Animals , Cyclohexanecarboxylic Acids/pharmacokinetics , Cyclohexanecarboxylic Acids/pharmacology , Dose-Response Relationship, Drug , Humans , Naphthyridines/pharmacokinetics , Naphthyridines/pharmacology , Nausea/chemically induced , Phosphodiesterase 4 Inhibitors/pharmacokinetics , Phosphodiesterase 4 Inhibitors/pharmacology , Rats , Solubility , Structure-Activity Relationship , Thermodynamics , Vomiting/chemically induced
3.
Bioorg Med Chem Lett ; 24(17): 4341-7, 2014 Sep 01.
Article in English | MEDLINE | ID: mdl-25065493

ABSTRACT

The optimisation of two series of 4-hydroxybenzothiazolone derived ß2-adrenoceptor agonists, bearing α-substituted cyclopentyl and ß-phenethyl amino-substituents, as inhaled long-acting bronchodilators is described. Analogues were selected for synthesis using a lipophilicity based hypothesis to achieve the targeted rapid onset of action in combination with a long duration of action. The profiling of the two series led to identification of the α-substituted cyclopentyl analogue 2 as the optimal compound with a comparable profile to the inhaled once-daily long-acting ß2-adrenoceptor agonist indacaterol. On the basis of these data 2 was promoted as the backup development candidate to indacaterol from the Novartis LABA project.


Subject(s)
Adrenergic beta-2 Receptor Agonists/administration & dosage , Adrenergic beta-2 Receptor Agonists/pharmacology , Benzothiazoles/administration & dosage , Benzothiazoles/pharmacology , Receptors, Adrenergic, beta-2/metabolism , Administration, Inhalation , Adrenergic beta-2 Receptor Agonists/chemistry , Animals , Benzothiazoles/chemistry , Dose-Response Relationship, Drug , Guinea Pigs , Molecular Structure
4.
J Med Chem ; 55(17): 7472-9, 2012 Sep 13.
Article in English | MEDLINE | ID: mdl-22889281

ABSTRACT

The solubility-driven optimization of a series of 1,7-napthyridine phosphodiesterase-4 inhibitors is described. Directed structural changes resulted in increased aqueous solubility, enabling superior pharmacokinetic properties with retention of PDE4 inhibition. A range of potent and orally bioavailable compounds with good in vivo efficacy in animal models of inflammation and reduced emetic potential compared to previously described drugs were synthesized. Compound 2d was taken forward as a clinical candidate for the treatment of COPD.


Subject(s)
Phosphodiesterase 4 Inhibitors/chemistry , Phosphodiesterase 4 Inhibitors/pharmacology , Animals , Cells, Cultured , Disease Models, Animal , Drug Design , Drug Evaluation, Preclinical , Humans , Magnetic Resonance Spectroscopy , Mice , Models, Molecular , Phosphodiesterase 4 Inhibitors/pharmacokinetics , Phosphodiesterase 4 Inhibitors/therapeutic use , Rats , Solubility , Vomiting/drug therapy
5.
Bioorg Med Chem Lett ; 20(17): 5302-7, 2010 Sep 01.
Article in English | MEDLINE | ID: mdl-20655218

ABSTRACT

The chiral synthesis of a 4-hydroxybenzothiazolone based series of beta(2)-adrenoceptor agonists is described. Using this methodology a library of N-substituted analogues were prepared for the rapid identification of leads with the potential to be fast onset and long-acting inhaled bronchodilators with improved therapeutic margins. The design of the library to achieve the targeted profile was based upon lipophilicity and metabolism based hypotheses. This approach identified beta-phenethyl, alpha-substituted cyclopentyl and monoterpene N-substituents to be of particular interest for further evaluation, as exemplified by structures 19, 29 and 33, respectively.


Subject(s)
Adrenergic beta-2 Receptor Antagonists/therapeutic use , Bronchodilator Agents/therapeutic use , Thiazoles/therapeutic use , Administration, Inhalation , Adrenergic beta-2 Receptor Antagonists/pharmacology , Bronchodilator Agents/administration & dosage , Bronchodilator Agents/pharmacology , Thiazoles/pharmacology
6.
Bioorg Med Chem Lett ; 20(3): 1219-24, 2010 Feb 01.
Article in English | MEDLINE | ID: mdl-20031406

ABSTRACT

The synthesis of two series of 4'-aza-carbocyclic nucleosides are described in which the 4'-substituent is either a reversed amide, relative to the carboxamide of NECA, or an N-bonded heterocycle. Using established purine substitution patterns, potent and selective examples of agonists of the human adenosine A(2A) receptor have been identified from both series. The propionamides 14-18 and the 4-hydroxymethylpyrazole 32 were determined to be the most potent and selective examples from the 4'-reversed amide and 4'-N-bonded heterocyclic series, respectively.


Subject(s)
Adenosine A2 Receptor Agonists , Aza Compounds/chemical synthesis , Carboxylic Acids/chemical synthesis , Nucleosides/chemical synthesis , Pyrimidine Nucleotides/chemical synthesis , Animals , Aza Compounds/metabolism , Aza Compounds/pharmacology , CHO Cells , Carboxylic Acids/metabolism , Carboxylic Acids/pharmacology , Cricetinae , Cricetulus , Drug Evaluation, Preclinical/methods , Humans , Nucleosides/metabolism , Nucleosides/pharmacology , Pyrimidine Nucleotides/metabolism , Pyrimidine Nucleotides/pharmacology , Rats , Receptor, Adenosine A2A/metabolism
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