Mitsuaki Ohtani

Synthesis and Biological Activity of Various Derivatives of a Novel Class of Potent, Selective, and Orally Active Prostaglandin D2 Receptor Antagonists. 2. 6,6-Dimethylbicyclo[3.1.1]heptane Derivatives

In an earlier paper, we reported that novel prostaglandin D(2) (PGD(2)) receptor antagonists having the bicyclo[2.2.1]heptane ring system as a prostaglandin skeleton were a potent new class of antiallergic agents and suppressed various allergic inflammatory responses such as those observed in conjunctivitis and asthma models. In the present study, we synthesized PGD(2) receptor antagonists having the 6,6-dimethylbicyclo[3.1.1]heptane ring system. These derivatives have the amide moiety, in contrast to those with the bicyclo[2.2.1]heptane ring system, which have the sulfonamide group. The derivatives having the 6,6-dimethylbicyclo[3.1.1]heptane ring also exhibited strong activity in PGD(2) receptor binding and cAMP formation assays. In in vivo assays such as allergic rhinitis, conjunctivitis, and asthma models, these series of derivatives showed excellent pharmacological profiles. In particular, compound 45 also effectively suppressed eosinophil infiltration in allergic rhinitis and asthma models. This compound (45, S-5751) is now being developed as a promising alternative antiallergic drug candidate.

Contraction of guinea pig lung parenchyma by pancreatic type phospholipase A2 via its specific binding site

Porcine pancreatic group I phospholipase A2 (PLA2‐I) induced contraction of guinea pig lung parenchyma in a concentration‐dependent manner. Its EC50 value was similar to theK d value calculated from the specific binding of125I‐labeled porcine PLA2‐I in the membrane fraction of guinea pig lung. Type‐specific action of PLA2s and homologous desensitization strongly implicated the involvement of PLA2‐I‐specific sites in the activation process. Throm☐ane A2 was found to be the main product from lung tissue by PLA2‐I action and the contractile response by PLA2‐I was specifically suppressed by throm☐ane A2 receptor antagonists and cyclooxygenase inhibitor, but not by leukotriene receptor antagonist and H1 blocker. These findings indicate that PLA2‐I‐induced contractile response may depend on the secondarily produced throm☐ane A2, thus providing a new aspect of PLA2‐I from the pathophysiological standpoint.

Enantiospecific synthesis of a rigid, C2 symmetric, chiral guanidine by a new and direct method

Abstract A broadly applicable method has been demonstrated for the efficient synthesis of chiral bicyclic guanidines such as 1 from chiral α-amino acids.

Total Synthesis of Terprenin, a Highly Potent and Novel Immunoglobulin E Antibody Suppressant

Regioselective halogenations and Suzuki reactions ensure proper linkage of the aromatic rings in two total syntheses of terprenin (1). Both routes make it possible to prepare 1 efficiently and in large quantity.

New γ-fluoromethotrexates modified in the pteridine ring: synthesis and in vitro immunosuppressive activity

Our continuing program to develop new antifolate drugs useful against rheumatoid arthritis led us to modify the pteridine ring of gamma-fluoromethotrexate. Pyrrolopyrimidine derivatives 1e and 1t were found to exhibit potent suppressive effects on the responses of both T and B cells to mitogens, although tetrahydropyridopyrimidine derivatives 2e and 2t and quinazoline derivatives 3e, 3t and 4e showed very weak suppressive activities. Thus, conversion of the pteridine ring of gamma-fluoromethotrexate to a pyrrolopyrimidine ring led to a new potential antirheumatic compound.

Practical synthesis of L-erythro- and L-threo-4-fluoroglutamic acids using aminoacylase

Abstract Enantiomerically pure L- erythro - and L- threo -4-fluoroglutamic acids 1a and 1b were conveniently prepared. The key steps in this synthesis relied upon separation of diastereomers of N -chloroacetyl-4-fluoroglutamic acid 5-methyl ester 7 by recrystallization and enzymatic resolution of enantiomers of the resulting 7(a+c) and 7(b+d) by aminoacylase. Protection of the γ-carboxyl group as a methyl ester was found to be crucial for this enzymatic reaction.

Totalsynthese von Terprenin, einem hochwirksamen Immunglobulin-E-Suppressivum

Regioselektive Halogenierungen und Suzuki-Reaktionen ermoglichen die richtige Verknupfung der aromatischen Ringe in zwei Totalsynthesen von Terprenin 1. Durch beide Reaktionswege kann 1 effizient und in groserer Menge erhalten werden.