Identification of a dual δ OR antagonist/µ OR agonist as a potential therapeutic for diarrhea-predominant Irritable Bowel Syndrome (IBS-d).

A small set of acyclic analogs 5 were prepared to explore their structure-activity relationships (SARs) relative to heterocyclic core, opioid receptor (OR) agonists 4. Compound 5l was found to have very favorable OR binding affinities at the δ and µ ORs (r K(i) δ=1.3 nM; r K(i) µ=0.9 nM; h K(i) µ=1.7 nM), with less affinity for the κ OR (gp K(i) κ=55 nM). The OR functional profile for 5l varied from the previously described dual δ/µ OR agonists 4, with 5l being a potent, mixed dual δ OR antagonist/µ OR agonist [δ IC(50)=89 nM (HVD); µ EC(50)=1 nM (GPI); κ EC(50)=1.6 µM (GPC)]. Compound 5l has progressed through a clinical Phase II Proof of Concept study on 800 patients suffering from diarrhea-predominant Irritable Bowel Syndrome (IBS-d). This Phase II study was recently completed successfully, with 5l demonstrating statistically significant efficacy over placebo.

Triazinediones as prokineticin 1 receptor antagonists. Part 1: SAR, synthesis and biological evaluation.

A series of guanidine triazinediones were identified as potent PK1 receptor antagonists. A compound in this series inhibited the PK1 invoked prosecretory response in rat ileum tissue.

Synthesis and SAR of pyridazinone-substituted phenylalanine amide alpha4 integrin antagonists.

Structural modification and cellular adhesion inhibition activities of pyridazinone-substituted phenylalanine amide alpha(4) integrin antagonists are described. Functionality requirements for the arylamide moiety and the carboxylic acid group were demonstrated. The study also revealed novel structure-activity relationships (SAR) for arylated pyridazinones. A correlation between bioavailability and permeability was also explored. A selected compound showed effectiveness in a mouse leukocytosis study.

Synthesis and biological evaluation of novel pyridazinone-based alpha4 integrin receptor antagonists.

A novel series of pyridazinone-functionalized phenylalanine analogues was prepared and evaluated for inhibition of cellular adhesion mediated by alpha4beta1/VCAM-1 and alpha4beta7/MAdCAM-1 interactions. Concise syntheses were developed and applied for exploration of structure-activity relationships pertaining to the pyridazinone ring as well as the N-acyl phenylalanine scaffold. Potent dual antagonists of alpha4beta1 and alpha4beta7 were generated from an amide subseries; antagonists selective for alpha4beta7 were identified from urea and carbamate-based subseries. The pharmacokinetic properties of selected members of the series have been determined in rats and demonstrate that the use of ester prodrugs and alterations to the amide linkage can lead to improved oral bioavailability in this series. An alpha4beta7-selective member of the carbamate subseries (36c), upon oral administration, demonstrated in vivo efficacy in the mouse DSS colitis model.

Identification of potent phenyl imidazoles as opioid receptor agonists.

Using previously reported opioid receptor (OR) agonist analogs 4a-c as starting points, the structure-activity relationship (SAR) for their related series has been further refined. This SAR study has led to the identification of 2,6-di-Me-Tyr (DMT) analogs 4h and 4j as the most potent OR agonist within the series. In addition, it was discovered that 4-(aminocarbonyl)-2,6-dimethyl-Phe is a reasonable bioisostere surrogate for the DMT moiety, as supported by the OR activities of compounds 4x and 4y.

Aza-bicyclic amino acid carboxamides as alpha4beta1/alpha4beta7 integrin receptor antagonists.

A series of N-carboxy, N-alkyl, and N-carboxamido azabicyclo[2.2.2]octane carboxamides were prepared and assayed for inhibition of alpha4beta1-VCAM-1 and alpha4beta7-MAdCAM-1 interactions. Potency and alpha4beta1/alpha4beta7 selectivity were sensitive to the substituent R1-R3 in the structures 6, 7, and 8. Several compounds demonstrated low nanomolar balanced alpha4beta1/alpha4beta7 in vitro activity. Two compounds were selected for in vivo leukocytosis studies and demonstrated increases in circulating lymphocytes up to 250% over control.

Rationale, design, and synthesis of novel phenyl imidazoles as opioid receptor agonists for gastrointestinal disorders.

A small series of novel, imidazoles 4 have been prepared that exhibit very good binding affinities for the delta and mu opioid receptors (ORs), as well as demonstrate potent agonist functional activity at the delta OR. Representative imidazole 4a (K(i) delta = 0.9 nM; K(i) mu = 55 nM; K(i) kappa = 124 nM; EC(50) delta =13-25 nM) was further profiled for OR related in vivo effects. Compound 4a reduced gastrointestinal (GI) propulsive motility in a dose-dependent and naloxone-reversible manner, based on the results of the mouse glass bead expulsion test (3, 5, and 10 mg/kg, ip) and the mouse fecal pellet output test (1 and 3 mg/kg, ip). Compound 4a showed no analgesic activity as measured by the mouse abdominal irritant test (MAIT) when dosed at 100 mg/kg, sc, but did show significant MAIT activity at doses of both 10 microg (40% inhibition) and 100 microg (100% inhibition) when dosed intracerebroventricularly (icv). Taken together, these in vivo results suggest that 4a acts peripherally when dosed systemically, and that these prototypical compounds may prove promising as medicinal leads for GI indications.

Tripeptidyl-peptidase II (TPP II) inhibitory activity of (S)-2,3-dihydro-2-(1H-imidazol-2-yl)-1H-indoles, a systematic SAR evaluation. Part 2.

We have systematically explored the structure-activity relationship (SAR) for a series of compounds 2 as inhibitors of tripeptidyl-peptidase II (TPP II), a serine protease responsible for the degradation of cholecystokinin-8 (CCK-8). This SAR evaluation of the core structure 2 suggest a fairly restrictive pharmacophore for such related structures, but has yielded a limited set of compounds (2b, 2c, 2d, 2s, and 2t) with potent TPP II inhibitory activity (IC(50) 4-11 nM).

Design, synthesis, and tripeptidyl peptidase II inhibitory activity of a novel series of (S)-2,3-dihydro-2-(4-alkyl-1H-imidazol-2-yl)-1H-indoles.

Butabindide, 1, was previously reported as a potent inhibitor (IC50 = 7 nM) of the serine protease enzyme tripeptidyl peptidase II (TPPII), an endogenous protease that degrades cholecystokinin-8 (CCK-8). We found that 1 has some inherent chemical instability, yielding diketopiperazine 2 fairly readily under mimicked physiological conditions. We therefore prepared imidazoles 3, which are void of 1's inherent instability, and have found that our novel analogues maintained comparable TPPII inhibitory activity (e.g.,for 3c, IC50 = 4 nM) as 1.