Thomas Kirkland

Synthesis of glutamic acid analogs as potent inhibitors of leukotriene A4 hydrolase.

Leukotriene B(4) (LTB(4)) is a potent pro-inflammatory mediator that has been implicated in the pathogenesis of multiple diseases, including psoriasis, inflammatory bowel disease, multiple sclerosis and asthma. As a method to decrease the level of LTB(4) and possibly identify novel treatments, inhibitors of the LTB(4) biosynthetic enzyme, leukotriene A(4) hydrolase (LTA(4)-h), have been explored. Here we describe the discovery of a potent inhibitor of LTA(4)-h, arylamide of glutamic acid 4f, starting from the corresponding glycinamide 2. Analogs of 4f are then described, focusing on compounds that are both active and stable in whole blood. This effort culminated in the identification of amino alcohol 12a and amino ester 6b which meet these criteria.

Investigational developments for the treatment of progesterone-dependent diseases

Background: Clinical evidence has shown that conditions such as uterine fibroids, endometriosis and breast cancer are progesterone-dependent diseases. Therefore, progesterone receptor (PR) antagonists and selective PR modulators (SPRMs) are under development for the treatment of these conditions. However, the first PR antagonists that became available exhibit insufficient selectivity or tolerability for the chronic administration required to treat these conditions. Despite initial setbacks, development of second-generation PR antagonists with better selectivity continues forward. Objective: In this review we would like to summarise prospects for using PR antagonists for the treatment of uterine fibroids, endometriosis and breast cancer, and to give an overview of the development of new steroidal and non-steroidal PR antagonists. Method: Available preclinical and clinical data and publications have been reviewed with the focus on scientific background and use in the three mentioned indications. Results/conclusion: Preclinical and clinical evidence demonstrated that PR antagonists and SPRMs are effective for the treatment of progesterone-dependent diseases. Future development will demonstrate if they can become important drugs.

Synthesis of N-alkyl glycine amides as potent inhibitors of leukotriene A4 hydrolase

The synthesis and biological evaluation of a series of N-alkyl glycine amide analogs as LTA(4)-h inhibitors and the importance of the introduction of a benzoic acid group to the potency and pharmacokinetic parameters of our analogs are described. The lead compound in the series, 4q, has excellent potency and oral bioavailability.

Discovery of novel and potent aryl diamines as leukotriene A4 hydrolase inhibitors

The synthesis and biological evaluation of a series of aryl diamines as inhibitors of LTA(4)-h inhibitors are described. The optimization which led to the identification of the optimal para-substitution on the diphenyl ether moiety and diamine spacer is discussed. The resulting compounds such as 3l have excellent enzyme and cellular potency as well as desirable pharmacokinetic properties.

Anti-tumor efficacy of the nucleoside analog 1-(2-deoxy-2-fluoro-4-thio-β-D-arabinofuranosyl) cytosine (4′-thio-FAC) in human pancreatic and ovarian tumor xenograft models

1‐(2‐Deoxy‐2‐fluoro‐4‐thio‐β‐D‐arabinofuranosyl) cytosine (4′‐thio‐FAC) is a deoxycytidine analog that has been shown previously to have impressive anti‐proliferative and cytotoxic effects in vitro and in vivo toward colorectal and gastric tumors. In our present studies, the pharmacokinetic behavior in nude mice and the effectiveness of 4′‐thio‐FAC against human pancreatic and ovarian tumor growth were assessed in comparison with standard chemotherapeutic agents. Potent in vitro anti‐proliferative effects were observed against pancreatic (Capan‐1, MIA‐PaCa‐2, BxPC‐3) and ovarian (SK‐OV‐3, OVCAR‐3, ES‐2) cancer cell lines with IC50 of 0.01–0.2 μM. In vivo anti‐tumor activity was evaluated in nude mice bearing subcutaneously (s.c.) implanted human pancreatic tumor xenografts or intraperitoneally (i.p.) disseminated human ovarian xenografted tumors. Oral daily administration of 4′‐thio‐FAC for 8–10 days significantly inhibited the growth of gemcitabine‐resistant BxPC‐3 pancreatic tumors and induced regression of gemcitabine‐refractory Capan‐1 tumors. 4′‐Thio‐FAC was also a highly effective inhibitor of ovarian peritoneal carcinomatosis. In the SK‐OV‐3 and ES‐2 ovarian cancer models, 4′‐thio‐FAC prolonged survival to a greater extent than that observed with gemcitabine. Furthermore, the superiority of 4′‐thio‐FAC to carboplatin and paclitaxel was demonstrated in the ES‐2 clear cell ovarian carcinoma model. Studies provide evidence that 4′‐thio‐FAC is a promising new alternative to gemcitabine and other chemotherapeutic drugs in the treatment of a variety of tumor indications, including pancreatic and ovarian carcinoma.