Hydantoin based inhibitors of MMP13--discovery of AZD6605.

Piperidine ether and aryl piperazine hydantoins are reported as potent inhibitors of MMP13. A medicinal chemistry campaign focused on replacing the reverse hydroxamate zinc binding group associated with historical inhibitors with a hydantoin zinc binding group then optimising MMP13 potency, solubility and DMPK properties whilst maintaining good selectivity over MMP14. A number of high quality candidates were progressed and following rat and dog safety evaluation, AZD6605 (3m) was identified as a candidate drug.

Orally active achiral N-hydroxyformamide inhibitors of ADAM-TS4 (aggrecanase-1) and ADAM-TS5 (aggrecanase-2) for the treatment of osteoarthritis.

A new achiral class of N-hydroxyformamide inhibitor of both ADAM-TS4 and ADAM-TS5, 2 has been discovered through modification of the complex P1 group present in historical inhibitors 1. This structural change improved the DMPK properties and greatly simplified the synthesis whilst maintaining excellent cross-MMP selectivity profiles. Investigation of structure-activity and structure-property relationships in the P1 group resulted in both ADAM-TS4 selective and mixed ADAM-TS4/5 inhibitors. This led to the identification of a pre-clinical candidate with excellent bioavailability across three species and predicting once daily dosing kinetics.

The design and synthesis of novel N-hydroxyformamide inhibitors of ADAM-TS4 for the treatment of osteoarthritis.

Two series of N-hydroxyformamide inhibitors of ADAM-TS4 were identified from screening compounds previously synthesised as inhibitors of matrix metalloproteinase-13 (collagenase-3). Understanding of the binding mode of this class of compound using ADAM-TS1 as a structural surrogate has led to the discovery of potent and very selective inhibitors with favourable DMPK properties. Synthesis, structure-activity relationships, and strategies to improve selectivity and lower in vivo metabolic clearance are described.

The synthesis of azadirachtin: a potent insect antifeedant.

We describe in full the first synthesis of the potent insect antifeedant azadirachtin through a highly convergent approach. An O-alkylation reaction is used to unite decalin ketone and propargylic mesylate fragments, after which a Claisen rearrangement constructs the central C8-C14 bond in a stereoselective fashion. The allene which results from this sequence then enables a second critical carbon-carbon bond forming event whereby the [3.2.1] bicyclic system, present in the natural product, is generated via a 5-exo-radical cyclisation process. Finally, using knowledge gained through our early studies into the reactivity of the natural product, a series of carefully designed steps completes the synthesis of this challenging molecule.

Amine-promoted, organocatalytic aziridination of enones.

A novel method is presented using N-N ylides (prepared by in situ amination of a tertiary amine) for the aziridination of a range of enone systems. The amine may be used sub-stoichiometrically, and promising levels of enantioselectivity are observed with quinine as promoter. [reaction: see text].

Synthesis of [6,n] cis-fused ring compounds via Cr-mediated dearomatisation-ring-closing metathesis.

cis-Fused [6,8], [6,7], [6,6] and [6,5] ring systems containing a cyclohexadiene ring unit, a cycloenone ring and a quaternary carbon at the ring junction were obtained in only two steps from [Cr(CO)3(eta6-p-methoxyphenyl oxazoline)]. The sequence proceeds via diastereoselective addition of three C-substituents across an arene double bond, followed by allylation and ring closing metathesis (RCM). RAMP-hydrazone and (R)-isopropyloxazoline were used as chiral auxiliaries to provide, after removal of the auxiliaries, the enantiomerically highly enriched [6,7] cis-fused system.