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Harlow, United Kingdom

Staben S.T.,Genentech | Ndubaku C.,Genentech | Blaquiere N.,Genentech | Belvin M.,Genentech | And 28 more authors.
Bioorganic and Medicinal Chemistry Letters | Year: 2013

A series of suitable five-membered heterocyclic alternatives to thiophenes within a thienobenzoxepin class of PI3-kinase (PI3K) inhibitors was discovered. Specific thiazolobenzoxepin 8-substitution was identified that increased selectivity over PI3Kβ. PI3Kβ-sparing compound 27 (PI3Kβ K i,app/PI3Kα Ki,app = 57) demonstrated dose-dependent knockdown of pAKT, pPRAS40 and pS6RP in vivo as well as differential effects in an in vitro proliferation cell line screen compared to pan PI3K inhibitor GDC-0941. A new structure-based hypothesis for reducing inhibition of the PI3K β isoform while maintaining activity against α, δ and γ isoforms is presented. © 2013 Elsevier Ltd. All rights reserved.

Hurley C.A.,9 Spire Green Center | Blair W.S.,Genentech | Bull R.J.,9 Spire Green Center | Chang C.,Genentech | And 23 more authors.
Bioorganic and Medicinal Chemistry Letters | Year: 2013

The identification of a novel fused triazolo-pyrrolopyridine scaffold, optimized derivatives of which display nanomolar inhibition of Janus kinase 1, is described. Prototypical example 3 demonstrated lower cell potency shift, better permeability in cells and higher oral exposure in rat than the corresponding, previously reported, imidazo-pyrrolopyridine analogue 2. Examples 6, 7 and 18 were subsequently identified from an optimization campaign and demonstrated modest selectivity over JAK2, moderate to good oral bioavailability in rat with overall pharmacokinetic profiles comparable to that reported for an approved pan-JAK inhibitor (tofacitinib). © 2013 Elsevier Ltd. All rights reserved.

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