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Gregori J Morriello,
Gary Chicchi,
Tricia Johnson,
Sander G Mills,
Julie Demartino,
Marc Kurtz,
K L C Tsao,
Song Zheng,
Xinchun Tong,
Emma Carlson, Karen Townson,
Alan Wheeldon,
Susan Boyce,
Neil Collinson,
Nadia Rupniak,
Robert J Devita
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ABSTRACT: Previously, we had disclosed a novel class of hNK(1) antagonists based on the 5,5-fused pyrrolidine core. These compounds displayed subnanomolar hNK(1) affinity along with good efficacy in a gerbil foot-tapping (GFT) model, but unfortunately they had low to moderate functional antagonist (IP-1) activity. To elaborate on the SAR of this class of hNK(1) compounds and to improve functional activity, we have designed and synthesized a new class of hNK(1) antagonist with a third fused ring. Compared to the 5,5-fused pyrrolidine class, these 5,5,5-fused tricyclic hNK(1) antagonists maintain subnanomolar hNK(1) binding affinity with highly improved functional IP-1 activity (<10% SP remaining). A fused tricyclic methyl, hydroxyl geminally substituted pyrrolizinone (compound 20) had excellent functional IP (<2% SP remaining), hNK(1) binding affinity, off-target selectivity, pharmacokinetic profile and in vivo activity. Complete inhibition of agonist activity was observed at both 0 and 24h in the gerbil foot-tapping model with an ID(50) of 0.02 mpk at both 0 and 24h, respectively.
Bioorganic & medicinal chemistry letters 10/2010; 20(19):5925-32. · 2.65 Impact Factor
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Michel Gallant,
Renee Aspiotis,
Stephen Day,
Rebecca Dias,
Daniel Dubé,
Laurence Dubé,
Richard W Friesen,
Mario Girard,
Daniel Guay,
Pierre Hamel, [......],
Jean-François Lévesque,
Susana Liu,
Dwight Macdonald,
Joseph Mancini,
Donald W Nicholson,
Angela Styhler, Karen Townson,
Kerry Waters,
Robert N Young,
Yves Girard
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ABSTRACT: The structure-activity relationship of a novel series of 8-biarylnaphthyridinones acting as type 4 phosphodiesterase (PDE4) inhibitors for the treatment of long-term memory loss and mild cognitive impairment is described herein. The manuscript describes a new paradigm for the development of PDE4 inhibitor targeting CNS indications. This effort led to the discovery of the clinical candidate MK-0952, an intrinsically potent inhibitor (IC(50)=0.6 nM) displaying limited whole blood activity (IC(50)=555 nM). Supporting in vivo results in two preclinical efficacy tests and one test assessing adverse effects are also reported. The comparative profiles of MK-0952 and two other Merck compounds are described to validate the proposed hypothesis.
Bioorganic & medicinal chemistry letters 09/2010; 20(22):6387-93. · 2.65 Impact Factor
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Gregori J Morriello,
Sander G Mills,
Tricia Johnson,
Mikhail Reibarkh,
Gary Chicchi,
Julie DeMartino,
Marc Kurtz,
P Davies,
K L C Tsao,
Song Zheng,
Xinchun Tong,
Emma Carlson, Karen Townson,
F D Tattersall,
Alan Wheeldon,
Susan Boyce,
Neil Collinson,
Nadia Rupniak,
Stephen Moore,
Robert J DeVita
[show abstract]
[hide abstract]
ABSTRACT: Previous work on human NK(1) (hNK(1)) antagonists in which the core of the structure is a 5,5-fused pyrrolizinone has been disclosed. The structural-activity-relationship studies on simple alpha- and beta-substituted compounds of this series provided several potent and bioavailable hNK(1) antagonists that displayed excellent brain penetration as observed by their good efficacy in the gerbil foot-tapping (GFT) model assay. Several of these compounds exhibited 100% inhibition of the foot-tapping response at 0.1 and 24h with ID(50)'s of less than 1 mpk. One particular alpha-substituted compound (2b) had an excellent pharmacokinetic profile across preclinical species with reasonable in vivo functional activity and minimal ancillary activity.
Bioorganic & medicinal chemistry letters 01/2010; 20(6):2007-12. · 2.65 Impact Factor
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Gregori J Morriello,
Robert J Devita,
Sander G Mills,
Jonathan R Young,
Peter Lin,
George Doss,
Gary G Chicchi,
Julie Demartino,
Marc M Kurtz,
Kwei-Lan C Tsao,
Emma Carlson, Karen Townson,
Alan Wheeldon,
Susan Boyce,
Neil Collinson,
Nadia Rupniak,
Stephen Moore
[show abstract]
[hide abstract]
ABSTRACT: Previous work on human NK(1) antagonists in which the core of the structure is a substituted pyrrolidine has been disclosed. These compounds showed good binding affinity and functional IP activity, however, many did not exhibit the necessary brain penetration for good in vivo activity. The discovery and preparation of a novel 5,5-fused pyrrolidine core is presented in this paper. This scaffold maintains the excellent binding affinity and functional IP activity of the previously reported compounds, but also exhibits excellent brain penetration as observed in a gerbil foot-tapping assay. The determination of the core structural stereochemistry, which eventually led to the final synthesis of a single active diastereomer, is described.
Bioorganic & medicinal chemistry 04/2008; 16(5):2156-70. · 2.82 Impact Factor
