Paul A. Tuthill

Potent, Orally Bioavailable Delta Opioid Receptor Agonists for the Treatment of Pain : Discovery of N,N-Diethyl-4-(5-hydroxyspiro-[chromene-2,4'-piperidine]-4-yl)benzamide (ADL5859)

Selective delta opioid receptor agonists are promising potential therapeutic agents for the treatment of various types of pain conditions. A spirocyclic derivative was identified as a promising hit through screening. Subsequent lead optimization identified compound 20 (ADL5859) as a potent, selective, and orally bioavailable delta agonist. Compound 20 was selected as a clinical candidate for the treatment of pain.

Spirocyclic Delta Opioid Receptor Agonists for the Treatment of Pain: Discovery of N,N-Diethyl-3-hydroxy-4-(spiro[chromene-2,4'-piperidine]-4-yl) Benzamide (ADL5747)

Selective, nonpeptidic delta opioid receptor agonists have been the subject of great interest as potential novel analgesic agents. The discoveries of BW373U86 (1) and SNC80 (2) contributed to the rapid expansion of research in this field. However, poor drug-like properties and low therapeutic indices have prevented clinical evaluation of these agents. Doses of 1 and 2 similar to those required for analgesic activity produce convulsions in rodents and nonhuman primates. Recently, we described a novel series of potent, selective, and orally bioavailable delta opioid receptor agonists. The lead derivative, ADL5859 (4), is currently in phase II proof-of-concept studies for the management of pain. Further structure activity relationship exploration has led to the discovery of ADL5747 (36), which is approximately 50-fold more potent than 4 in an animal model of inflammatory pain. On the basis of its favorable efficacy, safety, and pharmacokinetic profile, 36 was selected as a clinical candidate for the treatment of pain.

Antinociceptive activity of the selective iNOS inhibitor AR-C102222 in rodent models of inflammatory, neuropathic and post-operative pain

Nitric oxide generated by the nitric oxide synthase (NOS) isoforms contributes to pain processing. The selective inhibition of iNOS might represent a novel, therapeutic target for the development of antinociceptive compounds. However, few isoform‐selective inhibitors of NOS have been developed. The present experiments examined the anti‐inflammatory and antinociceptive activity of a selective inducible nitric oxide (iNOS) inhibitor, AR‐C102222, on arachidonic acid‐induced ear inflammation, Freunds complete adjuvant (FCA)‐induced hyperalgesia, acetic acid‐induced writhing, and tactile allodynia produced by L5 spinal nerve ligation (L5 SNL) or hindpaw incision (INC). AR‐C102222 at a dose of 100 mg/kg p.o., significantly reduced inflammation produced by the application of arachidonic acid to the ear, attenuated FCA‐induced mechanical hyperalgesia, and attenuated acetic acid‐induced writhing. In the L5 SNL and INC surgical procedures, tactile allodynia produced by both procedures was significantly reduced by 30 mg/kg i.p. of AR‐C102222. These data demonstrate that the selective inhibition of iNOS produces antinociception in different models of pain and suggest that the iNOS‐NO system plays a role in pain processing.

Design and Synthesis of Imidazopyrimidine Derivatives as Potent iNOS Dimerization Inhibitors

A series of imidazopyrimidine derivatives with the general formula I was synthesized and identified as potent inhibitors of iNOS dimer formation, a prerequisite for proper functioning of the enzyme. Stille and Negishi coupling reactions were used as key steps to form the carbon-carbon bond connecting the imidazopyrimidine core to the central cycloalkenyl, cycloalkyl and phenyl ring templates.