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1.
Bioorg Med Chem Lett ; 19(23): 6608-12, 2009 Dec 01.
Article in English | MEDLINE | ID: mdl-19846305

ABSTRACT

The introduction of an aryl ring onto the 4-position of the C-6 benzyl amino group of the Cdk inhibitor roscovitine (2), maintained the potent Cdk inhibition demonstrated by roscovitine (2) as well as greatly improving the antiproliferative activity. A series of C-6 biarylmethylamino derivatives was prepared addressing modifications on the C-6 biaryl rings, N-9 and C-2 positions to provide compounds that displayed potent cytotoxic activity against tumor cell lines. In particular, derivative 21h demonstrated a >750-fold improvement in the growth inhibition of HeLa cells compared to roscovitine (2).


Subject(s)
Antineoplastic Agents/pharmacology , Cyclin-Dependent Kinases/antagonists & inhibitors , Protein Kinase Inhibitors/pharmacology , Purines/pharmacology , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/chemistry , Cell Proliferation/drug effects , Drug Design , Drug Screening Assays, Antitumor , HeLa Cells , Humans , Molecular Structure , Protein Kinase Inhibitors/chemical synthesis , Protein Kinase Inhibitors/chemistry , Purines/chemical synthesis , Purines/chemistry , Roscovitine , Stereoisomerism , Structure-Activity Relationship
2.
J Med Chem ; 51(14): 4315-20, 2008 Jul 24.
Article in English | MEDLINE | ID: mdl-18578471

ABSTRACT

We have previously demonstrated that the prototypical GABA B receptor agonist baclofen inhibits transient lower esophageal sphincter relaxations (TLESRs), the most important mechanism for gastroesophageal reflux. Thus, GABA B agonists could be exploited for the treatment of gastroesophageal reflux disease. However, baclofen, which is used as an antispastic agent, and other previously known GABA B agonists can produce CNS side effects such as sedation, dizziness, nausea, and vomiting at higher doses. We now report the discovery of atypical GABA B agonists devoid of classical GABA B agonist related CNS side effects at therapeutic doses and the optimization of this type of compound for inhibition of TLESRs, which has resulted in a candidate drug ( R)- 7 (AZD3355) that is presently being evaluated in man.


Subject(s)
GABA Agonists/chemistry , GABA Agonists/pharmacology , GABA-B Receptor Agonists , Gastroesophageal Reflux/drug therapy , Animals , Dose-Response Relationship, Drug , GABA Agonists/therapeutic use , Humans , Magnetic Resonance Spectroscopy , Spectrometry, Mass, Fast Atom Bombardment
3.
J Med Chem ; 49(14): 4098-115, 2006 Jul 13.
Article in English | MEDLINE | ID: mdl-16821771

ABSTRACT

Amiloride (1), the prototypical epithelial sodium channel (ENaC) blocker, has been administered with limited success as aerosol therapy for improving pulmonary function in patients with the genetic disorder cystic fibrosis. This study was conducted to synthesize and identify more potent, less reversible ENaC blockers, targeted for aerosol therapy and possessing minimal systemic renal activity. A series of novel 2-substituted acylguanidine analogues of amiloride were synthesized and evaluated for potency and reversibility on bronchial ENaC. All compounds tested were more potent and less reversible at blocking sodium-dependent short-circuit current than amiloride. Compounds 30-34 showed the greatest potency on ENaC with IC(50) values below 10 nM. A regioselective difference in potency was found (compounds 30, 39, and 40), whereas no stereospecific (compounds 33, 34) difference in potency on ENaC was displayed. Lead compound 32 was 102-fold more potent and 5-fold less reversible than amiloride and displayed the lowest IC(50) value ever reported for an ENaC blocker.


Subject(s)
Bronchitis, Chronic/drug therapy , Cystic Fibrosis/drug therapy , Guanidines/chemical synthesis , Pyrazines/chemical synthesis , Sodium Channel Blockers/chemical synthesis , Sodium Channels/drug effects , Animals , Bronchi/drug effects , Bronchi/physiology , Combinatorial Chemistry Techniques , Dogs , Epithelial Sodium Channels , Guanidines/chemistry , Guanidines/pharmacology , Models, Molecular , Pyrazines/chemistry , Pyrazines/pharmacology , Respiratory Mucosa/drug effects , Respiratory Mucosa/physiology , Sodium Channel Blockers/chemistry , Sodium Channel Blockers/pharmacology , Sodium Channels/physiology , Stereoisomerism , Structure-Activity Relationship , Tissue Culture Techniques
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