Synthesis and evaluation of 8-oxoadenine derivatives as potent Toll-like receptor 7 agonists with high water solubility.

We report the discovery of novel series of highly potent TLR7 agonists based on 8-oxoadenines, 1 and 2 by introducing and optimizing various tertiary amines onto the N(9)-position of the adenine moiety. The introduction of the amino group resulted in not only improved water solubility but also enhanced TLR7 agonistic activity. In particular compound 20 (DSR-6434) indicated an optimal balance between the agonistic potency and high water solubility. It also demonstrated a strong antitumor effect in vivo by intravenous administration in a tumor bearing mice model.

Synthesis and biological evaluation of 8-oxoadenine derivatives as toll-like receptor 7 agonists introducing the antedrug concept.

Systemic administration of a Toll-like receptor 7 (TLR7) agonist is effective to in suppressing Th2 derived inflammation, however systemic induction of various cytokines such as IL-6, IL-12, and type I interferon (IFN) is observed. This cytokine induction would be expected to cause flu-like symptoms. We have previously reported adenine compounds (3, 4) as interferon inducing agents acting as TLR7 agonists. To identify potent anti-inflammatory compounds without systemic side effects, a labile carboxylic ester as an antedrug functionality onto the N(9)-benzyl group of the adenine was introduced. We found that 9e was a potent TLR7 agonist (EC(50) 50 nM) and rapidly metabolized by human plasma (T(1/2) 2.6 min) to the pharmacologically much less active carboxylic acid 16. Intratracheal administration of 9e effectively inhibited allergen-induced airway inflammation without inducing cytokines systemically. Therefore, the TLR7 agonist with antedrug characteristics 9e (SM-324405) is a novel candidate for immunotherapy of allergic diseases.

Hit-to-lead studies: the discovery of potent, orally active, thiophenecarboxamide IKK-2 inhibitors.

A hit-to-lead optimisation programme was carried out on the thiophenecarboxamide high throughput screening hits 1 and 2 resulting in the discovery of the potent and orally bioavailable IKK-2 inhibitor 22.

Hit-to-Lead studies: the discovery of potent adamantane amide P2X7 receptor antagonists.

A Hit-to-Lead optimisation programme was carried out on the adamantane high throughput screening hit 1 resulting in the discovery of a number of potent P2X(7) antagonists.

Hit-to-lead studies: the discovery of potent, orally bioavailable triazolethiol CXCR2 receptor antagonists.

A Hit-to-Lead optimisation programme was carried out on the high throughput screening hit, the triazolethiol 1, resulting in the discovery of the potent, orally bioavailable triazolethiol CXCR2 receptor antagonist 45.

1,2-Dihydro-4-quinazolinamines: potent, highly selective inhibitors of inducible nitric oxide synthase which show antiinflammatory activity in vivo.

The discovery of a novel class of nitric oxide synthase (NOS) inhibitors, 2-substituted 1,2-dihydro-4-quinazolinamines, and the related 4'-aminospiro[piperidine-4,2'(1'H)-quinazolin]-4'-amines is described. Members of both series exhibit nanomolar potency and high selectivity for the inducible isoform of the enzyme (i-NOS) relative to the constitutive isoforms in vitro. Efficacy in acute and chronic animal models of inflammatory disease following oral administration has also been demonstrated using these compounds.