ABSTRACT
Aniline 'headgroups' were synthesized and incorporated into an alkynyl thienopyrimidine series of EGFR and ErbB-2 inhibitors. Potent inhibition of enzyme activity and cellular proliferation was observed. In certain instances, protein binding was reduced and oral exposure was found to be somewhat improved relative to compounds containing the reference aniline.
Subject(s)
Aniline Compounds/chemical synthesis , ErbB Receptors/antagonists & inhibitors , Protein Kinase Inhibitors/chemical synthesis , Pyrimidines/chemical synthesis , Receptor, ErbB-2/antagonists & inhibitors , Administration, Oral , Aniline Compounds/administration & dosage , Aniline Compounds/pharmacology , Animals , Cell Line, Tumor , Cell Proliferation/drug effects , Drug Evaluation, Preclinical/methods , ErbB Receptors/metabolism , Growth Inhibitors/administration & dosage , Growth Inhibitors/chemical synthesis , Growth Inhibitors/pharmacology , Humans , Mice , Protein Kinase Inhibitors/administration & dosage , Protein Kinase Inhibitors/pharmacology , Pyrimidines/administration & dosage , Pyrimidines/pharmacology , Receptor, ErbB-2/metabolismABSTRACT
Two new series of potent and selective dual EGFR/ErbB-2 kinase inhibitors derived from novel thienopyrimidine cores have been identified. Isomeric thienopyrimidine cores were evaluated as isosteres for a 4-anilinoquinazoline core and several analogs containing the thieno[3,2-d]pyrimidine core showed anti-proliferative activity with IC(50) values less than 1 microM against human tumor cells in vitro.
Subject(s)
Antineoplastic Agents/pharmacology , Chemistry, Pharmaceutical/methods , ErbB Receptors/chemistry , Pyrimidines/chemistry , Receptor, ErbB-2/antagonists & inhibitors , Antineoplastic Agents/chemical synthesis , Cell Line, Tumor , Cell Proliferation , Drug Design , Drug Screening Assays, Antitumor , Enzyme Inhibitors/pharmacology , Humans , Inhibitory Concentration 50 , Lapatinib , Models, Chemical , Molecular Conformation , Quinazolines/pharmacologyABSTRACT
A novel class of pyrrolidinyl-acetyleneic thieno[3,2-d]pyrimidines has been identified which potently inhibit the EGFR and ErbB-2 receptor tyrosine kinases. Synthetic modifications of the pyrrolidine carbamate moiety result in a range of effects on enzyme and cellular potency. In addition, the impact of the absolute stereochemical configuration on cellular potency and oral mouse pharmacokinetics is described.
Subject(s)
Antineoplastic Agents/chemistry , ErbB Receptors/antagonists & inhibitors , Pyrimidines/pharmacology , Pyrrolidines/pharmacology , Receptor, ErbB-2/antagonists & inhibitors , Administration, Oral , Animals , Mice , Pharmacokinetics , Pyrimidines/chemical synthesis , Pyrrolidines/chemical synthesis , Structure-Activity RelationshipABSTRACT
Modification on a lead series of [1,4]oxazino[3,2-g]quinolin-7-ones at the 2-position led to selective androgen receptor modulators with improved in vivo activity. The most potent analog (-)-33a exhibited full maintenance of levator ani muscle at 3mg/kg and reduced activity on ventral prostate weight in a 2-week orally-dosed and orchidectomized rat maintenance assay.
Subject(s)
Anabolic Agents/pharmacology , Oxazines/pharmacology , Prostate/drug effects , Quinolones/pharmacology , Receptors, Androgen , Administration, Oral , Anabolic Agents/chemical synthesis , Androgen Receptor Antagonists , Androgens , Animals , Male , Models, Chemical , Orchiectomy , Organ Size/drug effects , Oxazines/chemical synthesis , Prostate/anatomy & histology , Quinolones/chemical synthesis , Rats , Rats, Sprague-Dawley , Structure-Activity Relationship , Testosterone/pharmacologyABSTRACT
Analysis of the x-ray crystal structure of mono-substituted acetylenic thienopyrimidine 6 complexed with the ErbB family enzyme ErbB-4 revealed a covalent bond between the terminal carbon of the acetylene moiety and the sulfhydryl group of Cys-803 at the solvent interface. The identification of this covalent adduct suggested that acetylenic thienopyrimidine 6 and related analogs might also be capable of forming an analogous covalent adduct with EGFR, which has a conserved cysteine (797) near the ATP binding pocket. To test this hypothesis, we treated a truncated, catalytically competent form of EGFR (678-1020) with a structurally related propargylic amine (8). An investigation of the resulting complex by mass spectrometry revealed the formation of a covalent complex of thienopyrimidine 8 with Cys-797 of EGFR. This finding enabled us to readily assess the irreversibility of various inhibitors and also facilitated a structure-activity relationship understanding of the covalent modifying potential and biological activity of a series of acetylenic thienopyrimidine compounds with potent antitumor activity. Several ErbB family enzyme and cell potent 6-ethynyl thienopyrimidine kinase inhibitors were found to form covalent adducts with EGFR.
Subject(s)
Alkynes/metabolism , Aniline Compounds/metabolism , ErbB Receptors/metabolism , Models, Molecular , Pyrimidines/metabolism , Animals , Cell Proliferation/drug effects , Crystallography, X-Ray , Dose-Response Relationship, Drug , Female , Isatin/analogs & derivatives , Isatin/metabolism , Mass Spectrometry , Mice , Mice, SCID , Molecular Structure , Pyrimidines/toxicity , Receptor Protein-Tyrosine Kinases/metabolism , Structure-Activity Relationship , Xenograft Model Antitumor AssaysABSTRACT
A series of androgen receptor modulators based on 8H-[1,4]oxazino[2,3-f]quinolin-8-ones was synthesized and evaluated in an androgen receptor transcriptional activation assay. The most potent analogues from the series exhibited single-digit nanomolar potency in vitro. Compound 18h demonstrated full efficacy in the maintenance of muscle weight, at 10 mg/kg, with reduced activity in prostate weight in an in vivo model of androgen action.
Subject(s)
Oxazines/chemical synthesis , Oxazines/pharmacology , Quinolones/chemical synthesis , Quinolones/pharmacology , Receptors, Androgen/drug effects , Animals , Cell Line , Dose-Response Relationship, Drug , Humans , Indicators and Reagents , Male , Models, Molecular , Orchiectomy , Rats , Receptors, Androgen/chemistry , Receptors, Progesterone/chemistry , Receptors, Progesterone/drug effects , Receptors, Somatotropin/chemistry , Receptors, Somatotropin/drug effects , Structure-Activity Relationship , Testosterone/bloodABSTRACT
Recent interest in orally available androgens has fueled the search for new androgens for use in hormone replacement therapy and as anabolic agents. In pursuit of this, we have discovered a series of novel androgen receptor modulators derived from 7H-[1,4]oxazino[3,2-g]quinolin-7-ones. These compounds were synthesized and evaluated in competitive binding assays and an androgen receptor transcriptional activation assay. A number of compounds from the series demonstrated single-digit nanomolar agonist activity in vitro. In addition, lead compound (R)-16e was orally active in established rodent models that measure androgenic and anabolic properties of these agents. In this assay, (R)-16e demonstrated full efficacy in muscle and only partially stimulated the prostate at 100 mg/kg. These data suggest that these compounds may be utilized as selective androgen receptor modulators or SARMs. This series represents a novel class of compounds for use in androgen replacement therapy.
