Peter J. Connolly

Recent advances towards the discovery of ORL-1 receptor agonists and antagonists

Since their discovery a decade ago, remarkable progress has been made toward understanding the biological function and significance of the opioid receptor-like-1 (ORL-1) receptor and its endogenous peptide ligand, nociceptin. The human nociceptin receptor, herein referred to as ORL-1, but also known as OP4 (the fourth member of opioid peptide receptor family) or nociceptin/orphanin FQ peptide (NOP) receptor, was first identified as an orphan opioid receptor with close homology to the classical μ-, κ-, and δ-opioid receptors. ORL-1 does not bind endogenous ligands of the other opioid receptors with high affinity, but instead prefers the 17 amino acid peptide nociceptin. The obvious homologies of ORL-1 to opioid receptors, and its ligand nociceptin to opioid peptide ligands, led to a period of intense investigation that resulted in a number of significant reports describing the biology of the receptor and ligand. The emerging pharmacological evidence from these reports suggests that ORL-1 agonists may be clinically useful for treatment of stress, anxiety, substance abuse (opioid and alcohol), anorexia, cachexia, cough, asthma, and possibly neuropathic pain/allodynia. The peripheral effects of nociceptin suggest that agonists may have utility in the treatment of gastrointestinal motility disorders, water retention, and hypertension. ORL-1 antagonists may be useful in enhancing cognitive function and treating locomotor disorders such as Parkinsonism. In addition to research into the fundamental biology of ORL-1 and nociceptin, noteworthy advances have been made in the discovery of new peptide and non-peptide agonists and antagonists of the ORL-1 receptor leading to a better understanding of its involvement in a variety of biological processes. This review highlights the rationale for the development of ORL-1 ligands and recent progress made by different research groups towards the development of peptidic and non-peptidic ORL-1 agonists or antagonists over the last four years. To add perspective on the commercial potential of this research area, the development status of advanced new molecules is addressed together with any pharmacological characterisation of these entities.

Synthesis and evaluation of 2,7-diamino-thiazolo[4,5-d] pyrimidine analogues as anti-tumor epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors

2,7-Diamino-thiazolo[4,5-d]pyrimidine analogues were synthesized as novel epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors. Representative compounds showed potent and selective EGFR inhibitory activities and inhibited in vitro cellular proliferation in EGFR-overexpressing human tumor cells. The synthesis and preliminary biological, physical, and pharmacokinetic evaluation of these thiazolopyrimidine compounds are reported.

4-Amino-6-arylamino-pyrimidine-5-carbaldehyde hydrazones as potent ErbB-2/EGFR dual kinase inhibitors.

Members of a novel class of 4-amino-6-arylamino-pyrimidine-5-carbaldehyde hydrazones were identified as potent dual ErbB-2/EGFR kinase inhibitors using concept-guided design approach. These compounds inhibited the growth of ErbB-2 over-expressing human tumor cell lines (BT474, N87, and SK-BR-3) in vitro. Compound 15 emerged as a key lead and showed significant ability to inhibit growth factor-induced receptor phosphorylation in SK-BR-3 cells (IC(50)=54 nM) and cellular proliferation in vitro (IC(50)=14, 58, and 58 nM for BT474, N87, and SK-BR-3 respectively). The X-ray co-crystal structure of EGFR with a close analog (17) was determined and validated our design rationale.

Discovery of novel 4-amino-6-arylaminopyrimidine-5-carbaldehyde oximes as dual inhibitors of EGFR and ErbB-2 protein tyrosine kinases

We herein disclose a novel series of 4-aminopyrimidine-5-carbaldehyde oximes that are potent and selective inhibitors of both EGFR and ErbB-2 tyrosine kinases, with IC(50) values in the nanomolar range. Structure-activity relationship (SAR) studies elucidated a critical role for the 4-amino and C-6 arylamino moieties. The X-ray co-crystal structure of EGFR with 37 was determined and validated our design rationale.

N-Hydroxyurea and hydroxamic acid inhibitors of cyclooxygenase and 5-lipoxygenase

Two series of compounds (1 and 2) having structural features of the dual COX/5-LO inhibitor tepoxalin and the 5-LO inhibitor ABT-761 were prepared. Many of these hybrid compounds are potent COX and 5-LO inhibitors; two compounds (1a and 2t) inhibit eicosanoid biosynthesis in an ex vivo assay.

(Arylpiperazinyl)cyclohexylsufonamides: Discovery of α1a/1d-selective adrenergic receptor antagonists for the treatment of Benign Prostatic Hyperplasia/Lower Urinary Tract Symptoms (BPH/LUTS)

Benign prostatic hyperplasia/lower urinary tract symptoms (BPH/LUTS) can be effectively treated with alpha(1) adrenergic receptor antagonists. Unfortunately, currently marketed alpha(1) blockers produce CV-related side effects that are caused by the subtype non-selective nature of the drugs. To overcome this problem, it was postulated that an alpha(1a/1d) subtype-selective antagonist would bring more benefit for the treatment of BPH/LUTS. As a continuation of our effort to develop selective alpha(1a/1d) ligands, a series of (phenylpiperazinyl)cyclohexylureas was synthesized and evaluated for the ability to bind to three cloned human alpha(1)-adrenergic receptor subtypes. Several trans isomers were shown to have equal affinity for both alpha(1a), and alpha(1d) subtypes, with 14- to 47-fold selectivity versus the alpha(1b) subtype and >15-fold selectivity versus dopamine D(2).

A novel 5-[1,3,4-oxadiazol-2-yl]-N-aryl-4,6-pyrimidine diamine having dual EGFR/HER2 kinase activity: design, synthesis, and biological activity.

A novel 5-[1,3,4-oxadiazol-2-yl]-N-aryl-4,6-pyrimidine diamine was synthesized and found to have potent dual EGFR/HER2 kinase inhibitory activity. The structure-based drug design of this molecule as well as the kinase and cellular inhibition of HER2 kinase dependent cell lines will be discussed.

7-[1H-Indol-2-yl]-2,3-dihydro-isoindol-1-ones as dual Aurora-A/VEGF-R2 kinase inhibitors: Design, synthesis, and biological activity

A novel series of 7-[1H-indol-2-yl]-2,3-dihydro-isoindol-1-ones designed to be inhibitors of VEGF-R2 kinase was synthesized and found to potently inhibit VEGF-R2 and Aurora-A kinases. The structure-based design, synthesis, and initial SAR of the series are discussed.

Synthesis and progesterone receptor binding affinity of substituted 1-phenyl-7-benzyl-4,5,6,7-tetrahydro-1H-indazoles

Abstract Research directed toward the discovery of non-steroidal ligands for steroid receptors led to the preparation of a series of substituted 1-phenyl-7-benzyltetrahydroindazole-3-carboxaldehydes. Appropriately substituted 3-formyl analogs (4) were found to bind with high affinity to progesterone receptors and showed agonist activity in human T47D cells but were inactive in several in vivo models for progestational activity.

4-Aminopyrimidine-5-carbaldehyde oximes as potent VEGFR-2 inhibitors. Part II

A series of 4-aminopyrimidine-5-carbaldehyde oxime was discovered to have potent VEGFR-2 inhibitory activity. Described here are the chemistry for analogue synthesis and SAR study results. The PK properties, kinase profiling, and in vivo efficacy study for compound 4b are also discussed.