Clara I. Villamil

Orally Active MMP-1 Sparing α-Tetrahydropyranyl and α-Piperidinyl Sulfone Matrix Metalloproteinase (MMP) Inhibitors with Efficacy in Cancer, Arthritis, and Cardiovascular Disease

α-Sulfone-α-piperidine and α-tetrahydropyranyl hydroxamates were explored that are potent inhibitors of MMPs-2, -9, and -13 that spare MMP-1, with oral efficacy in inhibiting tumor growth in mice and left-ventricular hypertrophy in rats and in the bovine cartilage degradation ex vivo explant system. α-Piperidine 19v (SC-78080/SD-2590) was selected for development toward the initial indication of cancer, while α-piperidine and α-tetrahydropyranyl hydroxamates 19w (SC-77964) and 9i (SC-77774), respectively, were identified as backup compounds.

Synthesis and activity of selective MMP inhibitors with an aryl backbone

A series of novel, MMP-1 sparing arylhydroxamate sulfonamides with activity against MMP-2 and -13 is described.

α-Amino-β-sulphone hydroxamates as potent MMP-13 inhibitors that spare MMP-1

Abstract A series of α-amino-β-sulphone hydroxamates was prepared and evaluated for potency versus MMP-13 and selectivity versus MMP-1. Various substituents were employed on the α-amino group (P1 position), as well as different groups attached to the sulphone group extending into P1′. Low nanomolar potency was obtained for MMP-13 with selectivity versus MMP-1 of >1000× for a number of analogues.

Selective, orally active MMP inhibitors with an aryl backbone

This letter describes SAR exploration and rat PK optimization of a series of novel, MMP-1 sparing aryl hydroxamate sulfonamides with activity against MMP-2 and MMP-13.

Enantioselective Synthesis of Dual Serotonergic Azanoradamantane SC-52491

Abstract A racemic synthesis of azanoradamantane (±) -3 was accomplished via Yamamotos MAD-catalyzed Diels-Alder protocol. Subsequently, a scalable asymmetric synthesis of azanoradamantane benzamide SC-52491 was carried out employing Helmchens asymmetric Diels-Alder methodology to construct all four contiguous asymmetric centers with the correct relative stereochemistry and in 99.3% e.e.

Enantioselective synthesis of dual 5-HT45-HT3 serotonergic azanoradamantane SC-52491

Abstract A racemic synthesis of azanoradamantane (±) -3 was accomplished via Yamamotos MAD-catalyzed Diels-Alder protocol. Subsequently, a scalable asymmetric synthesis of azanoradamantane benzamide SC-52491 was carried out employing Helmchens asymmetric Diels-Alder methodology to construct all four contiguous asymmetric centers with the correct relative stereochemistry and in 99.3% e.e.

1,3,4-Trisubstituted Pyrrolidinones as Scaffolds for Construction of Peptidomimetic Cholecystokinin Antagonists

Abstract A new series of cholecystokinin (CCK) antagonists are described which utilizes a new 1,3,4-trisubstituted pyrrolidinone as a scaffold for appending specific amino acid R group mimics (Figure 1). Compound 1A and 1E (SC-50998) exhibit potent nanomolar IC 50 values in a CCK-A receptor binding assay. Compound 1E behaves as a competitive antagonist in vitro and is orally active.

MMP-13 selective α-sulfone hydroxamates: a survey of P1' heterocyclic amide isosteres.

Seeking compounds preferentially potent and selective for MMP-13, we reported in the preceding Letter on a series of hydroxamic acids with a flexible benzamide tail groups.(1a) Here, we replace the amide moiety with non-hydrolyzable heterocycles in an effort to improve half-life. We identify a hydroxamate tetrazole 4e that spares MMP-1 and -14, shows >400-fold selectivity versus MMP-8 and >600-fold selectivity versus MMP-2, and has a 4.8 h half-life in rats. X-ray data (1.9 Å) for tetrazole 4c is presented.

Serotonin 5-HT4 agonist activity of a series of meso-azanoradamantane benzamides

A series of meso-amino(methyl)azanoradamantane benzamides has been prepared and evaluated for 5-HT4 agonism activity in the rat tunica muscularis mucosae (TMM) assay. Compound 8i is the most potent 5-HT4 agonist in the series, with an EC50 of 217 nM.

Design and synthesis of agonists and antagonists of the serotonin 5-HT4 receptor subtype

Publisher Summary This chapter discusses the design and synthesis of agonists and antagonists of the serotonin 5-HT4 receptor subtype. Serotonin is unsurpassed among monoamine neurotransmitters in the number of receptor subtypes reported to-date. Fourteen subtypes of seven major serotonin receptor classes have been identified in the central nervous system, the peripheral nervous system, myeloid/immune cell types, and smooth musculature of mammals. For some time, it has been known that serotonin exerts profound effects in the enteric nervous system (ENS). It has been previously appreciated that 5-HT4 agonism requires a planar orientation of the amide bond and the aromatic ring system. This feature contributes to the potent agonist properties of the ortho-alkoxy benzamides i, wherein intramolecular hydrogen-bonding maintains such a planar conformation.