Ligaya M. Simpkins

Dual metalloprotease inhibitors. I. constrained peptidomimetics of mercaptoacyl dipeptides

Abstract A series of benzo-fused lactams were incorporated as conformationally restricted dipeptide mimetics of Ala-Pro in dual-acting ACE/NEP inhibitors 1 and 2. The result of this modification led to compounds possessing excellent inhibitory potency versus ACE and NEP both in vitro and in vivo.

N-Formyl hydroxylamine containing dipeptides: generation of a new class of vasopeptidase inhibitors

Four primary zinc-binding pharmacophores (thiols, carboxylates, phosphorus acids, and hydroxamates) have been utilized in generating inhibitors of zinc metalloproteases such as ACE, NEP, the MMPs, and ECE. Although compounds which inhibit the activity of both ACE and NEP (vasopeptidase inhibitors, VPIs) have been reported which incorporate a thiol, carboxylate, or phosphorus acid pharmacophore, the generation of hydroxamate based vasopeptidase inhibitors has remained elusive. Herein we report the first potent vasopeptidase inhibitors which were generated from the incorporation of conformationally restricted dipeptide mimetics to an N-formyl hydroxylamine zinc-binding group. Compounds such as 13c and 13d are among the most potent in this series, exhibiting in vitro activity comparable to other classes of inhibitors.

Dual metalloprotease inhibitors. II. Effect of substitution and stereochemistry on benzazepinone based mercaptoacetyls

Abstract A structure-activity study of dual-acting ACE/NEP inhibitor 1A was initiated in order to ascertain what parameters effect in vitro activity versus ACE and NEP. Unlike NEP, ACE was found to be remarkably tolerant to a wide variety of permutations with respect to both the lactam nucleus and the pharmacophore side chain.

Pyridine amides as potent and selective inhibitors of 11β-hydroxysteroid dehydrogenase type 1

Several series of pyridine amides were identified as selective and potent 11beta-HSD1 inhibitors. The most potent inhibitors feature 2,6- or 3,5-disubstitution on the pyridine core. Various linkers (CH(2)SO(2), CH(2)S, CH(2)O, S, O, N, bond) between the distal aryl and central pyridyl groups are tolerated, and lipophilic amide groups are generally favored. On the distal aryl group, a number of substitutions are well tolerated. A crystal structure was obtained for a complex between 11beta-HSD1 and the most potent inhibitor in this series.

Generation of 3,8-substituted 1,2,4-triazolopyridines as potent inhibitors of human 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD-1).

A series of pyridyl amide/sulfonamide inhibitors of 11β-HSD-1 were modified to incorporate a novel 1,2,4-triazolopyridine scaffold. Optimization of substituents at the 3 and 8 position of the TZP core, with a special focus on enhancing metabolic stability, resulted in the identification of compound 38 as a potent and metabolically stable inhibitor of the enzyme.

N-Aryl-oxazolidin-2-imine Muscle Selective Androgen Receptor Modulators Enhance Potency through Pharmacophore Reorientation

A novel selective androgen receptor modulator (SARM) scaffold was discovered as a byproduct obtained during synthesis of our earlier series of imidazolidin-2-ones. The resulting oxazolidin-2-imines are among the most potent SARMs known, with many analogues exhibiting sub-nM in vitro potency in binding and functional assays. Despite the potential for hydrolytic instability at gut pH, compounds of the present class showed good oral bioavailability and were highly active in a standard rodent pharmacological model.

DUAL METALLOPROTEASE INHIBITORS. III: UTILIZATION OF BICYCLIC AND MONOCYCLIC DIAZEPINONE BASED MERCAPTOACETYLS

Abstract A series of bicyclic and monocyclic diazepinones were incorporated as conformationally restricted dipeptide surrogates in mercaptoacetyl dipeptide dual-acting ACE/NEP inhibitors. A comparison was made between these two classes of compounds as well as with the previously disclosed ACE/NEP inhibitor 1. Compound 2a was found to exhibit high potency versus both enzymes in vitro as well as in vivo.

Synthesis, SAR, and atropisomerism of imidazolopyrimidine DPP4 inhibitors.

The synthesis and SAR of aminomethyl-substituted imidazolopyrimidine DPP4 inhibitors bearing varied pendant aryl groups is described. Compound 1, which exists as a separable mixture of non-interconvertible atropisomers was used as the starting point for investigation. The effects of substituent pattern and type as well as stereochemical effects on inhibitor potency are discussed.