W E Perkins

Bio: W E Perkins is an academic researcher from G. D. Searle & Company. The author has contributed to research in topics: Misoprostol & Prostaglandin. The author has an hindex of 8, co-authored 13 publications receiving 2022 citations.

Synthesis and biological evaluation of the 1,5-diarylpyrazole class of cyclooxygenase-2 inhibitors: identification of 4-[5-(4-methylphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benze nesulfonamide (SC-58635, celecoxib).

Abstract: A series of sulfonamide-containing 1,5-diarylpyrazole derivatives were prepared and evaluated for their ability to block cyclooxygenase-2 (COX-2) in vitro and in vivo. Extensive structure-activity relationship (SAR) work was carried out within this series, and a number of potent and selective inhibitors of COX-2 were identified. Since an early structural lead (1f, SC-236) exhibited an unacceptably long plasma half-life, a number of pyrazole analogs containing potential metabolic sites were evaluated further in vivo in an effort to identify compounds with acceptable pharmacokinetic profiles. This work led to the identification of 1i (4-[5-(4-methylphenyl)-3-(trifluoromethyl)- H-pyrazol-1-yl]benzenesulfonamide, SC-58635, celecoxib), which is currently in phase III clinical trials for the treatment of rheumatoid arthritis and osteoarthritis.

Polymeric drug delivery system

Abstract: A drug delivery system adapted to release an effective amount of a drug at pH values of about 1 to 7 without releasing a significant amount of the drug at pH values of about 7 and above, the system comprising a polymeric material and a drug covalently bonded to the polymeric material through a pH sensitive covalent bond capable of being cleaved in the pH range of 1 to about 7.

Catalytic functionalization of polymers : a novel approach to site specific delivery of misoprostol to the stomach

Abstract: The application of functionalized polymers to site-directed delivery of the antiulcer prostaglandin, misoprostol, is described. By use of homogeneous catalysis, the simple polymer, polybutadiene, was modified to incorporate the specialized requirements for controlled delivery of misoprostol to the stomach. An acid labile silyl ether bond to the C-11 hydroxyl of misoprostol was installed as the primary rate determining step for drug release, and a series of analogs, in which the steric hindrance about the silicon atom was varied, was prepared and evaluated for in vitro release rates, efficacy against indomethacin induced gastric damage and diarrheagenic activity. The diisopropylsilyl analog, the slowest releasing system studied, showed efficacy equal to misoprostol against indomethacin-induced gastric damage and no diarrhea at the highest dose tested.

Polymer delivery of the active isomer of misoprostol: a solution to the intestinal side effect problem.

Abstract: SC-53450 is a new polybutadiene-based polymer system with an acid labile diisopropyl silyl ether linker to which the active isomer of misoprostol (SC-30249) is attached covalently at position C-11. It was studied in rats and dogs to define its profile of gastrointestinal effects relative to misoprostol-hydroxypropyl methylcellulose (HPMC) and the systemic availability of prostaglandin from the polymer. Results of rat studies indicate that SC-53450 has a spectrum of mucosal protective activity similar to misoprostol-HPMC, being protective against indomethacin-induced gastric, cysteamine/indomethacin-induced duodenal and indomethacin-induced lower small bowel damage. SC-53450, in contrast to misoprostol-HPMC, was not diarrheagenic in the rat when administered intragastrically. The observation that SC-53450 is more than 4 times more potent than misoprostol-HPMC suggests the possibility of sustained gastric availability of the prostaglandin SC-30249. SC-53450 exhibited gastric antisecretory activity in histamine-stimulated gastric fistula dogs and protected against acidified aspirin-induced gastric damage in normal fasted beagles. Rat and dog experiments indicate that little, if any, polymer-derived prostaglandin is available systemically, suggesting SC-53450 will have reduced abuse potential in abortion induction. SC-53450 is a potential candidate to replace the present misoprostol formulation in the marketplace for the prevention of nonsteroidal anti-inflammatory drug-induced gastric damage.

Click Chemistry: Diverse Chemical Function from a Few Good Reactions.

Abstract: Examination of nature's favorite molecules reveals a striking preference for making carbon-heteroatom bonds over carbon-carbon bonds-surely no surprise given that carbon dioxide is nature's starting material and that most reactions are performed in water. Nucleic acids, proteins, and polysaccharides are condensation polymers of small subunits stitched together by carbon-heteroatom bonds. Even the 35 or so building blocks from which these crucial molecules are made each contain, at most, six contiguous C-C bonds, except for the three aromatic amino acids. Taking our cue from nature's approach, we address here the development of a set of powerful, highly reliable, and selective reactions for the rapid synthesis of useful new compounds and combinatorial libraries through heteroatom links (C-X-C), an approach we call "click chemistry". Click chemistry is at once defined, enabled, and constrained by a handful of nearly perfect "spring-loaded" reactions. The stringent criteria for a process to earn click chemistry status are described along with examples of the molecular frameworks that are easily made using this spartan, but powerful, synthetic strategy.

Fluorine in medicinal chemistry.

Abstract: It has become evident that fluorinated compounds have a remarkable record in medicinal chemistry and will play a continuing role in providing lead compounds for therapeutic applications. This tutorial review provides a sampling of renowned fluorinated drugs and their mode of action with a discussion clarifying the role and impact of fluorine substitution on drug potency.

Cyclooxygenases 1 and 2

Abstract: Cyclooxygenase (COX), first purified in 1976 and cloned in 1988, is the key enzyme in the synthesis of prostaglandins (PGs) from arachidonic acid. In 1991, several laboratories identified a product from a second gene with COX activity and called it COX-2. However, COX-2 was inducible, and the inducing stimuli included pro-inflammatory cytokines and growth factors, implying a role for COX-2 in both inflammation and control of cell growth. The two isoforms of COX are almost identical in structure but have important differences in substrate and inhibitor selectivity and in their intracellular locations. Protective PGs, which preserve the integrity of the stomach lining and maintain normal renal function in a compromised kidney, are synthesized by COX-1. In addition to the induction of COX-2 in inflammatory lesions, it is present constitutively in the brain and spinal cord, where it may be involved in nerve transmission, particularly that for pain and fever. PGs made by COX-2 are also important in ovulation and in the birth process. The discovery of COX-2 has made possible the design of drugs that reduce inflammation without removing the protective PGs in the stomach and kidney made by COX-1. These highly selective COX-2 inhibitors may not only be anti-inflammatory but may also be active in colon cancer and Alzheimer’s disease.