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Chromene COX-2 Inhibitor Project

Parnership between GIBH and Drs. Mark Obukowicz and John Talley

Non-steroidal anti-inflammatory drugs (NSAIDs) inhibit both COX-1 and COX-2 and have been a mainstay in clinical medicine for the treatment of inflammation and inflammatory pain. COX-2-selective inhibitors (coxibs) widely replaced traditional NSAIDs because they retained comparable efficacy, while limiting toxicity to the gastrointestinal tract (Fosslien, 2005). Also, coxibs were initially hypothesized to limit renal and cardiovascular side effects, however, this proved not to be the case (Harris and Breyer, 2006). In the kidney, COX-2 is expressed constitutively in certain regions (e.g., macula densa) and is highly regulated in response to changes in blood volume. COX-2 metabolites (e.g., PGE2 and PGI2) play a mechanistic role in renin release, sodium excretion, and the maintenance of renal blood flow and glomerular filtration rate (Hao and Breyer, 2008). Coxibs fell into disfavor within clinical medicine because initial data linked them to cardiovascular risks of stroke and myocardial infarction compared with traditional NSAIDs (Sanghi et al., 2006). However, compelling data from two recent clinical analyses (Trell et al., 2011; Olsen et al., 2011) have shown that similar and even short-term cardiovascular risks were associated with both coxib sand traditional NSAIDs and that the risks appeared to be drug-dependent rather than class-dependent. These data are instilling renewed interest in coxibs, particularly with coxibs that have a unique pharmacological profile, which could thus fulfill an unmet medical need. Examples include treating pain and inflammation without further compromising renal function in renal compromised patients1 and in treating or preventing certain types of cancer.2

The chromene pharmacophore represents a novel class of coxibs that could fulfill an unmet medical need in inflammation and cancer. The chromene coxibs have a carboxylate moiety and do not bind in the hydrophobic binding pocket of the COX-2 active site. As a class, they have been shown to confer potency, efficacy, and selectivity on par with the diaryl heterocyclic coxibs (eg, celecoxib, valdecoxib, rofecoxib, and etoricoxib) in the standard rat models of inflammation and pain.The chromene coxib clinical candidate, SC-75416 (see below), was shown to be differentiated from the diaryl heterocyclic coxibs in that it conferred reduced tactile allodynia in a rat model of neurophathic pain. Also, in a phase 2 clinical trial, SC-75416 was shown to confer superior efficacy compared with ibuprofen in mitigating acute dental pain.A testing scheme has been implemented and the synthesis of novel and potentially superior chromene coxibanalogs has been initiated.The chromene pharmacophore may prove to provide advantages over the existing coxibs for the treatment of inflammation and pain, especially for those patients who are inadequately served by the analgesic medications available today. As a class, the chromene coxibs have the potential to be renal-sparing and there by mitigate coxib-induced hypertension due to their intrinsic and distinct structural, pharmacological, and physiochemical properties. These combine dproperties, if borne out, could allow Chinese sFDAapproval, as well as world-wide approval, including the United States, with first-in-class and best-in-class status.

Tragara Pharmaceuticals, Inc. recently reported the results of APRICOT-L, a Phase 2 study with its coxib, apricoxib (structurally related to celecoxib), at a poster session on June 6, 2011 at the American Society for Clinical Oncology meeting in Chicago (www.tragarapharma.com/APRiCOT-L). In a subset of non-small cell lung cancer patients having a high level of urinary PGEM, a metabolite of PGE2, apricoxib in combination with Roche Holdings/AstellaPharma’sTarceva (erlotinib) significantly prolonged the time to tumor progression.  

The original chromene analog conferred acute anti-inflammatory activity in vivo by an unknown mechanism. Reverse pharmacology was utilized to demonstrate that the anti-inflammatory activity was due to the original chromene analog being metabolized in vivo to the chromene coxib referred to as compound 1 in Wang et al. (2010a). Identification of the chromene coxib classlead to initiation of aso-called 3rd Generation COX-2 Inhibitor Project within Searle/Pharmacia (following celecoxib [1st generation coxib] and valdecoxib [2nd generation coxib]). That effort culminated with the identification of five chromene coxib clinical candidates, namely, SD-8381 (first clinical candidate; Wang et al., 2010a); SC-75416 (second clinical candidate and clinical lead candidate having a shorter human half-life than SD-8381; Wang et. al., 2010b); and chromene coxib analogs 18c-S, 29b-S, and 34b-S (human micro-dose candidates and clinical back-up candidates to SC-75416; Wang et al., 2010c).

Pre-clinical profiles: 
All of the chromene coxibclinical candidates were shown to be relatively potent, efficacious, and selective COX-2 inhibitors in in vitro/ex vivo assays (e.g., rhCOX-1/rhCOX-2 enzyme assays, human cell-based assays, and the human whole blood assay) and inin vivo models of inflammation/pain (e.g., rat carrageenan air pouch, rat carrageenan footpad edema/hyperalgesia, and rat adjuvant-induced arthritis) (Wang et al., 2010a; Wang et al., 2010b; Wang et al., 2010c).In addition, their high degree of aqueous solubility affords the potential for parenteral formulation. Crystallographic analyses showed that the chromene coxib analogs bound to the COX-2 active site in two binding modes that were flipped by 180 degrees, depending on the length of the 7-position substituents. The chromene coxib clinical candidates,SD-8381 (Wang et al., 2010a) and SC-75416 (Wang et al., 2010b), have relatively short 7-position substituents and, thus, only the active S isomers bind in a mode comparable to that of diclofenac, a carboxylic acid-containing NSAID that binds in the “inverted” binding mode compared with the profen class ofcarboxylic acid-containing NSAIDs (e.g., flurbiprofen). In contrast,the chromene coxib analog, 23d (Wang et al., 2010c),has a lengthy 7-alkoxy position substituent and, thus, only the active R isomer binds in a mode that is flipped 180 degrees compared with SD-8381 and SC-75416. Unlike the diaryl heterocyclic coxibs (e.g., celecoxib, valdecoxib,rofecoxib, and etoricoxib), neither binding mode utilizes the side pocket, demonstrating that binding within the side pocket is not an absolute requirement to provide COX-2 selectivity. In this regard, the chromene coxib clinical candidates are similar to Novartis’s lumiracoxib, a coxib analog of diclofenac that binds in the “inverted” NSAID binding mode (Esser et al., 2005).SC-75416, in particular,was subjected to extensive pre-clinical profiling (Gierse et al., 2008). SC-75416 was shown to confer potency, efficacy, and selectivity on par with the diaryl heterocyclic coxibs in the standard rat models of inflammation and pain. However, unlike the diaryl heterocylic coxibs, SC-75416 conferred reduced tactile allodynia in a rat model of neurophathic pain (i.e., sciatic nerve ligation).

Clinical profiles:
SD-8381 advanced into a phase 1 clinical trial, but was dropped from further development because of its long half-life of 360 hours (Wang et al., 2010a). SC-75416 was identified as a backup clinical candidate that advanced into a phase 1 clinical trial, where it had an acceptable half-life of 34 hours (Wang et al., 2010b). In an ensuing phase 2 clinical trial (Kowalski et al., 2008), SC-75416 provided a fast onset of action andsuperior efficacy for the treatment of acute dental pain compared with ibuprofen (best standard-of-care).Three additional backup clinical candidates, 18c-S, 29b-S, and 34b-S, were advanced into a human micro-dose clinical trial where they were shown to have half-lives of 57, 13, and 11 hours, respectively (Wang et al., 2010c).

Project goals: 
(1)The overall goal is to identify novel and potentially superior chromene coxibs for the treatment of acute and chronic pain/inflammation and, possibly, cancer. (2) The initial goal is to identify a chromene coxib clinical candidate within 18 months for the treatment of acute dental pain in China. Acute dosing (i.e., ≤7 days) in patients who have not suffered a previous myocardial infarction will be targeted initially in order to minimize coxib/NSAID-mediated cardiovascular risks (i.e., hypertension, edema, myocardial infarction, and stroke). (3) In parallel, the renal- and hypertension-sparing properties of the lead chromene coxibs will be evaluated. (4) Chronic indications of pain/inflammation (e.g., OA and RA) will be explored in China if the clinical chromene coxib candidate is renal- and hypertension-sparing. (5) Select cancer indications that have a COX-2 component will be explored China.


Dr. John Talley
Professional qualifications:

Distinguished Scientist, Inventor, and Researcher with over 25 years experience and a broad background in organic and medicinal chemistry with prestigious pharmaceutical firms throughout the U.S.

Regarded as a highly effective researcher who has made “key” research contributions from 1986-present:

Distinguished Scientist, Ironwood Pharmaceuticals, Inc.
Senior Vice-President of Drug Discovery, Ironwood Pharmaceuticals, Inc.
Senior Research Fellow, Pharmacia, Inc.
Inventor of the COX-2 inhibitor, celecoxib (Celebrex™) – commercialized in 1999
Inventor of the COX-2 inhibitor, valdecoxib (Bextra™) – commercialized in 2001
Inventor of the injectable COX-2 inhibitor, parecoxib (Dynastat™) – commercialized in 2002
Co-inventor of the COX-2 inhibitor, deracoxib (Deramaxx™) – commercialized in 2002
Inventor of the COX-2 inhibitor, mavacoxib (Trocoxil™) – commercialized in 2008
Co-inventor of the hydroxyethyl sulfonamide isostere for HIV-protease inhibition
amprenavir (Agenerase™) in 1999; fosamprenavir (Lexiva®) in 2004 – licensed from Searle/Monsanto and commercialized by Vertex Pharmaceuticals and GlaxoSmithKline; and darunavir (Prezista™) – commercialized in 2006 by Johnson & Johnson
Inventor on more than 200 US patents

Dr.  Mark Obukowicz
Professional qualifications:

Senior Research Fellow, Pfizer Global Research and Development, with >26 years experience in drug discovery
Discoverer of novel and proprietary (Pfizer’s intellectual property) chromene series of COX-2-selective inhibitors
Initiator and project leader of two new dissociated glucocorticoid receptor ligands (“Holy Grail” of glucocorticoid biology), which have advanced from pre-clinical discovery to Phase I/II clinical development in the last five years
Initiator and first project leader of the Land-Based Omega-3 Fatty Acid Project (Stearidonic Acid-Soybean Oil), which is progressing towards commercialization under the auspices of a Monsanto/Solae partnership
Proven track record as a drug hunter/people leader – innovation, leadership, and achievement
Recipient of many awards, including the 2009 PGRD Individual Achievement Award, 2008 PGRD Team Achievement Award, and 2005 Portanova Award (PhD level, Pfizer-St. Louis)
Primary author/senior author/major contributor on 28 publications and inventor on 34 US patents

Team Leader at GIBH:

Zhang Yanmei Ph.D.

Dr. Zhang, received her B.S. in Chemistry from Shandong University in 1995. She studied Organofluorine Chemistry in Shanghai Institute of Organic Chemistry, CAS as a Master student. In 1998, she joined National Center for Drug Screening and worked on the setup of compound library by combinatorial chemistry and natural product purification. Dr. Zhang obtained her Ph.D. from Technical University of Munich, Germany in 2004. Her work focused on organic catalysis and methodology. After graduation, Dr. Zhang continued to study and work in UK and USA. Before joining GIBH, Dr. Zhang worked at the drug discovery center of University of California, San Diego (UCSD) Cancer Center with Prof. Dennis Carson on the design and synthesis of AdSS inhibitors and TLR7 antagonists and the formulation of correspondent active small molecules, especially in liposome form. In March 2011, Dr. Zhang joined GIBH and is responsible for design and synthesis of COX-2 inhibitors and setup of laboratory for dosage form and regulation of laboratory for drug analysis.


Esser R, Berry C, Du Z, et al. (2005) Preclinical pharmacology of lumiracoxib: A novel selective inhibitor of cyclooxygenase-2. Br. J.Pharmacol. 144:538-550.

Fosslien E (2005) Review: Cardiovascular complications of non-steroidal anti-inflammatory drugs. Ann. Clin. Lab. Sci. 35(4):347-385.

Gierse J, Mickols M, Leahy K, et al. (2008) Evaluation of COX-1/COX-2 selectivity and potency of a new class of COX-2 inhibitors. Eur. J.Pharmacol. 588:93-98.

Hao, C-M and Breyer, MD (2008) Physiological regulation of prostaglandins in the kidney.Annu. Rev. Physiol. 70:357-377.

Harris, RC and Breyer, MD (2006) Update on cyclooxygenase-2 inhibitors.Clin. J. Am. Soc. Nephrol. 1:236-245.

Kowalski KG, Olson S, Remmers AE, and Hutmacher MM. (2008) Modeling and simulation to support dose selection and clinical development of SC-75416, a selective COX-2 inhibitor for the treatment of acute and chronic pain. Clin.Pharmacol.Ther. 83(6):857-866.

Sanghi S, MacLaughlin EJ, Jewell, CW, et al. (2006) Cyclooxygenase-2 inhibitors: A painful lesson. Cardiovasc.Hematol.Disord. Drug Targets 6:83-98.

Schjerning-Olsen AM, Fosbol EL, Lindhardsen J, et al. (2011) Duration of treatment with nonsteroidal drugs and impact on risk of death and recurrent myocardial infarction in patients with prior myocardial infarction. Circulation 123:2226-2235.

Trell, S, Reichenbach S, Wandel S, et al. (2011) Cardiovascular safety of non-steroidal anti-inflammatory drugs: network meta-analysis. BMJ 342:c7086.

Wang JL, Carter J, Kiefer JR, et al. (2010a) The novel benzopyran class of selective cyclooxygenase-2 inhibitors – Part 1: The first clinical candidate. Bioorg. Med. Chem. Let. 20(23):7155-7158.

Wang JL, Limburg D, Graneto MJ, et al. (2010b) The novel benzopyran class of selective cyclooxygenase-2 inhibitors – Part 2: The 2nd clinical candidate with a shortened human half-life. Bioorg.Med. Chem. Let. 20(23):7159-7163.

Wang JL, Aston K, Limburg D, et al. (2010c) The novel benzopyran class of selective cyclooxygenase-2 inhibitors – Part 3: The three microdose candidates. Bioorg. Med. Chem. Let. 20(23):7164-7168.


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